Steroids and process for preparing the same

ABSTRACT

Novel steroids are described together with processes of making them and pharmaceutical compositions containing them. The steroids have pharmaceutical activity, especially antiinflammatory activity. They are all 2-Bromo-6β-fluoro-pregna-1,4-diene-3,20-diones.

This is a division of application Ser. No. 553,124, filed Feb. 26, 1975now U.S. Pat. No. 4,226,862.

The present invention relates to a new class of steroids having goodanti-inflammatory activity, to processes of making them and topharmaceutical compositions containing them.

Many steroids having anti-inflammatory activity upon topical and/orsystemic administration are known and some of them have quitesatisfactory anti-inflammatory activity. Unfortunately they all tend togive undesired side effects. For instance they may disturb the mineralbalance in the subject to which they are administered, for example theymay reduce the potassium and/or sodium balance and they may affectadversely the adrenals function.

Accordingly their application has to be conducted with caution.

It has been our object to produce novel steroids that have very goodanti-inflammatory activity, preferably higher than that of most or allknown steroids, and which have very low or no side effects, preferablywhen measured in absolute terms but in particular when measured as thetherapeutic ratio, i.e. the ratio of the active dose that is required toachieve the desired anti-inflammatory activity to the minimum dose thatincurs undesired side effects.

We have now found that 2-Bromo-6β-fluoro-pregna-1,4-diene-3,20-dioneshave high anti-inflammatory activity and at the same avoid completely orat least minimise the undesirable side effects of known steroidcompounds. The preferred novel compounds of the invention have thegeneral formula ##STR1##

wherein

X represents Br, Cl, or OQ;

Y represents Br, Cl, F or H;

R₁ represents OQ;

R₂ represents OQ;

R₃ represents H, αOQ, αCH₃ or βCH₃, and

the radicals Q, which may be the same or different, are selected from Hand

acyl radicals, or the groups OQ in the 16 and 17 positions or in the 17and 21 positions may together form a cyclic ketal, cylic acetal orcyclic alkyl orthoester, and pharmaceutically acceptable salts or esterswith those compounds wherein at least one radical OQ is a carboxylic oran inorganic acid radical. The salts are preferably water soluble andare preferably with an alkali metal, for example sodium or potassium.The esters are preferably with an aliphatic, aryl, arylaliphatic orcycloaliphatic group. The OQ group of R₁ can be also an alkylorthoester.

Typical values of aliphatic radicals suitable as the esterifying radicalin a dicarboxylic acyl group are alkyl, preferably containing up to 7carbon atoms, and alkenyl. Particularly preferred are alkyl containingup to 4 carbon atoms, especially methyl, ethyl and propyl. Typicalcycloaliphatic are cycloalkyl radicals containing 5 to 8 carbon atoms,for example cyclopentyl and cyclohexyl. Typical arylaliphatic radicalsare phenyl alkyl radicals, for example where alkyl is as describedabove, for instance benzyl. Typical aryl radicals are those containing aphenyl ring, for example unsubstituted phenyl.

When Q is acyl, OQ thus being an ester radical, Q may be the radical ofan inorganic acid, for example sulphuric acid or phosphoric acid, or anorganic acid, for example a sulphonic acid or a carboxylic acid,including aliphatic, alicyclic, aromatic, arylaliphatic and heterocycliccarboxylic acids, including carboxylic acids such as thiocarboxylicacids and amino carboxylic acids. Preferred carboxylic acids are formicacid, acetic acid, chloroacetic acid, trifluoroacetic acid, propionicacid, butyric acid, valeric acid, trimethylacetic acid, diethylaceticacid, caproic acid, crotonic acid, enanthic acid, caprylic acid, capricacid, palmitic acid, undecanic acid, undecylenic acid, oxalic acid,succinic acid, glutaric acid, pimelic acid, tartaric acid, maleic acid,lactic acid, carbamic acid, glycine, alkoxy carboxylic acids,hexahydrobenzoic acid, cyclopentylpropionic acids, cyclohexylaceticacid, cyclohexylbutyric acids, benzoic acid, phthalic acid, phenylaceticacid, phenylpropionic acids, furane-2-carboxylic acid, nicotinic acidand isonicotinic acid. Preferred sulphonic acids are methanesulphonicacid and toluenesulphonic acid.

Particularly preferred acyl radicals are those derived from acetic acid,trimethylacetic acid, propionic acid, β-phenylpropionic acid,α-phenylpropionic acid, valeric acid and dicarboxylic acids, for examplesuccinic acid.

It is often preferred that in R₁ Q shall be an acyl group as describedabove, particularly the preferred carboxylic acyl groups as describedabove, since 21-esters have particularly good biological activity. It isoften preferred that when X represents OQ, Q shall be hydrogen.

Any convenient cyclic ketals or cyclic acetals may be formed at the16,17 or 17,21 positions but are preferably acetonides or 17,21methylene dioxy derivatives. Suitable cyclic orthoesters that may beformed at these positions include the 17,21 methylorthoacetate, the17,21 ethylorthopropionate, the 17,21 methylorthobenzoate and the 17,21methylorthovalerate.

One preferred class of compounds of the invention are those wherein R₃represents H or αOQ, especially OH. Another preferred class of compoundsof the invention are those wherein R₃ represents α or β methyl, mostpreferably α methyl.

It is often preferred that Y should be halogen. X can also be halogenand thus some preferred compounds of the invention have both X and Yrepresenting halogen, usually both representing chlorine or bothrepresenting bromine. However, it is generally preferred that Y shallrepresent halogen and X shall represent OQ, preferably OH. Preferredvalues of Y are bromine and, especially, fluorine. Thus particularlypreferred compounds of the invention are 9-α-halo (especially fluoro)11-β-hydroxy compounds.

It is of course already well known to make pregna-1,4-diene-3,20-dionecompounds. It is also known to produce a few 2-bromo steroids. Further,it is well known to make 6-α-fluoro steroids. There have been somereferences to the production of 6-β-fluoro steroids in the literaturebut it seems to have been generally considered in the art that6-β-fluoro steroids are inferior pharmaceutically to 6-α-fluorosteroids. The combination of 2-bromo with 6-β-fluoro in pregna1,4-diene-3,20-diones appear to be new and gives good anti-inflammatoryactivity with low or negligible side effects as discussed above.

The novel compounds of the invention have good anti-inflammatoryactivity. This activity can be exhibited upon conventional methods ofadministration, for example topically and systemically. Some compoundsgive best results topically while others give best results systemically,for instance when taken orally as is preferred. Because of the very highactivity possessed by preferred compounds of the invention much lowerdosages can be used than are useful with known anti-inflammatorysteroids; even at conventional dosages preferred compounds of theinvention have much less, and generally no, side effects compared withknown anti-inflammatory steroids.

The compounds of the invention are useful for treatment of a widevariety of inflammatory conditions, for example in the treatment ofinflammatory conditions of the skin, eyes and ears of humans and ofvaluable domestic animals, as well as contact dermatitis and otherallergic reactions and also possess valuable antirheumatoid arthriticproperties.

Therapeutic compositions of the invention comprise a compound of theinvention together with a pharmaceutically acceptable liquid or solidcarrier. Any therapeutically acceptable and effective concentration ofthe compound in the composition may be used. Any suitable compositionmay be prepared, according to the chosen manner of administration.Suitable compositions include pills, tablets, capsules, solutions,syrups or elixirs for oral use, liquid forms of the types used to makeinjectable compositions of the natural and synthetic cortical steroidhormones, and topical compositions, for example in the form ofointments, creams and lotions.

The compositions may also include coacting antibiotics, germicides orother materials forming advantageous combination therewith.

The local anti-inflammatory activity has been evaluated in rats by thecotton-pellet induced granuloma test, applying the compound directly tothe pellet.

All the new compounds of the present invention show a remarkableanti-inflammatory activity without undesirable side effects on thethymus and on the body weight increase even at very high concentrations(40 micrograms/pellet).

The most active compounds inhibit the cotton-pellet induced granuloma atdoses as low as 0.002-0.1 micrograms/pellet whereasFluocinolone-16,17-acetonide evokes the same effect at a dose of 0.5-2micrograms/pellet. Other compounds of the present invention are activeat doses ranging from 0.1 to 2 micrograms/pellet whereas Betamethasone17-valerate is active at a dose of 5-20 micrograms/pellet. Some othercompounds of the present invention display activity at doses higher than2 micrograms/pellet. Hydrocortisone acetate shows the same activity atabout 100-200 micrograms/pellet.

The systemic anti-inflammatory activity has been evaluated in rats bythe cotton-pellet induced granuloma test, giving the compounds orallyfor 8 days. The most active compounds show activity at doses rangingfrom 0.01 to 0.1 mg/kg b.w. In the same experimental conditionsBetamethasone (alcohol or phosphate) shows activity at doses of about0.05-0.1 mg/kg b.w. while Hydrocortisone acetate and Methylprednisoloneare active at doses ranging from 10 to 50 mg/kg b.w. Most of thecompounds of the present invention have, on this test, no inhibitingaction on adrenals weight and a thymolitic or body weight reducingactivity lower than that displayed by the most active already knownsteroids.

The compounds of the invention can be made by various processesincluding the following:

1. Compounds where R₁ and R₂ are as defined previously, R₃ is hydrogenor α or β methyl or α OQ (preferably OH), X is OQ (preferably OH) and Yis Br can be made by dissolving the corresponding 9,11-unsaturatedcompound in an organic solvent such as methylene chloride, tertiarybutyl alcohol, dioxane, tetrahydrofurane, tertiary amyl alcohol or thelike, and by reacting this at room temperature with an hypobromous acidreleasing agent, which includes N-bromoacetamide, N-bromosuccinimide,1,3-dibromo-5,5-dimethyl-hydantoin or the like, in the presence of anacid such as perchloric acid, diluted sulfuric acid and the like.Normally the bromination is conducted at room temperature, betweenfifteen and thirty degrees centigrade. The reaction period may vary fromabout five minutes to one hour.

At the conclusion of the desired reaction the excess hypobromous acid isdestroyed by the addition of sulfites or hydrosulfites, sodium sulfitebeing normally employed. The resulting compound can be isolated from thereaction mixture by adding an excess of water and extracting the productwith organic solvents or by recovering the precipitated compound byfiltration.

2. Compounds in which R₁ and R₂ are as defined above, R₃ is hydrogen orα or β methyl or αOQ (preferably OH) and X and Y are both bromine orboth chlorine can be made by reacting the corresponding 9,11-unsaturedcompound with a chlorinating or brominating agent. Suitable agents areN-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide,N-bromoacetamide, N-chloroacetamide or the like.

The reaction is preferably conducted in an organic solvent such as loweraliphatic carboxylic acids, for example glacial acetic acid,diethylacetic acid, propionic acid or butyric acid, or in ethersolvents, for example tetrahydrofurane or dioxane, or in halogensolvents for example methylene chloride or chloroform, or in a mixtureof these solvents. The reaction is carried out at temperature of 0° to50° C., preferably ambient temperature in the presence of halogen-anionssuch as chloro or bromo in the form of corresponding alkali halides,preferably potassium or lithium chloride.

3. Compounds where R₁ and R₂ are as defined above, R₃ is hydrogen or αor β methyl or αOQ (preferably OH), X is OQ, preferably OH, and Y ishalogen (preferably F and Cl) can be made by reacting the corresponding9,11-epoxide (for instance prepared by dehydrobromination with analkaline carbonate solution of the 9-bromo-11-hydroxy compound preparedas described above) with hydrogen halide, namely HF or HCl. This may begenerated in situ but preferably is introduced as aqueous solution. Thesteroid is first dissolved in an organic solvent such astetrahydrofurane, methylene chloride and the like. The halogenationreaction is operative at room temperature but is preferably conducted atlower temperatures, such as zero to minus eighty degrees centigrade,with continuous stirring. After the reaction is completed, the mixtureis poured into water and neutralized with diluted base, such as dilutedsodium or potassium hydroxide, or a bicarbonate such as sodiumbicarbonate, potassium bicarbonate or the like. The reaction mixture isthen extracted in the usual manner, such as with methylene chloride, andthe resulting compound is recovered in a purified form byrecrystallization or chromatography.

4. Compounds in which R₁, X and Y are all as defined for Formula A, andR₂ and R₃ are both OH may be made by oxidising the corresponding 16,17unsaturated compound. Any oxidising agents known for oxidising a doublebond in a steroid to produce a dihydroxy compound can be used, forexample potassium permanganate. The reaction is preferably conducted inan acidic aqueous organic solution such as glacial acetic acid or formicacid in aqueous acetone at a temperature of -20° to +50° C. The reactionmay be terminated by adding a reducing agent, such as sodium sulphite.

5. Any compound of the invention in which any or all of X, R₁, R₂ or R₃represent OQ where Q is H can be made by hydrolysing the correspondingcompound where Q is acyl. Hydrolysis can be conducted under acidicconditions, for example in the presence of an acid such as hydrochloricacid, or under alkaline conditions, for example in the presence of analkali such as sodium hydroxide or sodium carbonate, in an aqueous,organic or aqueous organic solvent, for example a lower alcohol, attemperature of 0° to 100° C., preferably under reflux.

Acetates in 11 position usually are extremely resistant to hydrolysis.

6. Any compound of the invention in which one or more of X, R₁, R₂ andR₃ represents OQ where Q is an acyl radical can be made by esterifyingthe corresponding compound in which Q represents hydrogen.Esterification can be conducted by reaction with the appropriate acidhalide or acid anhydride in pyridine or other suitable organic solvent,preferably a basic solvent. The reaction is best conducted in organicsolvent at temperatures of 0° to 100° C. preferably under reflux. Thisprocess is best carried out on the 16 or 21 positions, the hydroxy groupin the 11 an 17 positions usually remaining unchanged during thereaction. The 17 and 11 positions require acid anhydrides with mineralacids as catalyst.

The 17 monoesters are prepared by a mineral or organic acid hydrolysisof cyclic 17,21-alkyl orthoesters. The cyclic 17,21-alkyl orthoestersare prepared from the corresponding 17,21-dihydroxy by exchange reactionwith trimethyl orthoesters in the presence of an acid catalyst. Theorthoesterification steps is carried out at temperature ranging from 60°to 130° C. and preferably around 100°-110° C. for a period of 4-24hours. The orthoesters thus obtained are then hydrolized with a mineralor organic acid to give the 17-monoesters.

The cyclic 16,17-alkyl orthoesters are also prepared from thecorresponding diols with trimethylorthoesters in the presence of an acidcatalyst. The orthoesterification step is carried out at temperatureranging from 20° to 30° C. for a period of 1-2 hours.

7. Compounds of the invention in which OQ in the 16 and 17 positions orin the 17 and 21 positions represent a cyclic acetal or a cyclic ketalcan be made by treating a suspension or solution of the correspondingdiols in the desired aldehyde or ketone (or an organic solvent, if thealdehyde or ketone is a solid) with an acid catalyst (e.g., perchloricacid, p-toluene sulfonic acid and hydrochloric acid), neutralizing theacid and recovering the cyclic acetal or ketal derivative formed.

The reaction is preferably carried out a temperature within the rangefrom about 15° to 60° C. It is usually completed within a period fromabout one hour to eighteen hours.

The 17,21-cyclic acetals and ketals are prepared by an acid catalyzedinterchange reaction between the corresponding diols and lower alkylacetals of aliphatic, cycloaliphatic or arylaliphatic aldehydes orketones.

The reaction is best conducted in organic solvent at temperatures from20° to 100° C. preferably under reflux.

The 16,17 unsaturated compound described above as the starting materialfor the production of the 16,17 dihydroxy compound may be made bydehydration of the corresponding 17-hydroxy compound in which R₃ is H sothat all the processes described above can be considered to start fromthe 9,11-unsaturated compound wherein R₃ is hydrogen or methyl. We showin FIG. 1 a suitable reaction scheme for making these compounds havingFormula VIII, starting from the known compound I. ##STR2##

A suitable way of carrying out the reaction scheme in FIG. 1 is nowdescribed. In this the known starting material11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (I) or its known16α or 16β methyl analogue, is first ketalized to produce the 3-ketal(II). Ethylene glycol, in the presence of p-toluenesulfonic acid orpyridine hydrochloride, is the preferred ketalizing agent. Formation ofthe ketal is accompanied by migration of the double bound from the 4,5to the 5,6 position.

The epoxidation of the 5(6) double bound of the compound II with aperacid (perbenzoic or mono perphthalic acid or other known epoxidizingagents) produces the corresponding 5α,6β-epoxide (III). A mixture ofboth the α and β epoxides is produced in this epoxidation reaction, andthe mixture can be separated by crystallization. The α-epoxide III isemployed in the next step, which is an epoxide opening reaction in whichthe11α,17α,21-trihydroxy-3,3-ethylene-dioxy-6α,6α-oxido-pregnane-20-one-21-acetate(III) is reacted with hydrofluoric acid to produce the corresponding6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(IV).

The buffered bromination of the compound IV stops to the2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(V).

Addition of methanesulphonyl chloride to the compound V produces the2α,-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate(VI).

Treatment of the mesylate VI with acetic anhydride and perchloric acidproduces the2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate(VII), which is converted, by bromination in acetic acid containingpotassium or sodium acetate as the base, into2,2-dibromo-6β-fluoro-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate(VII bis).

The combination of certain metal halides, particularly lithium chlorideand bromide in hot dimethylformamide, is particularly effective indehydrobromination of compound VII bis to the corresponding triene VIII,2-bromo-6β-l-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate.Other amide solvents, such as dimethyl-acetamide and N-formylpiperidinecan be used in place of dimethylformamide. A modification involves theuse of an excess of lithium carbonate in dimethylformamide.

A particularly important step in this scheme is the formation of thecompound of formula V. Accordingly a further feature of the inventionresides in the bromination of compounds of formula IV, as well as the 11and/or 17 caters and/or 21 hydroxy derivatives to produce thecorresponding 2α bromo compounds. The introduction of the 2α bromocompound at this stage appars to fix the configuration of the 6β-fluorogroup so that it is stable during the subsequent reactions in thesteroid molecule.

Compounds of formula V, as well as the 11 and/or 17 caters and/or 21hydroxy analogues are novel compounds, as also are compounds of each offormulae II to VIII inclusive.

Convenient ways of carrying out the processes 1 to 7 listed above areshown in the reaction scheme in FIG. II ##STR3##

The reaction of the compound VIII with hydrobromous acid produces thecorresponding 9α-bromo comound IX. When this 9α-bromo compound isreacted with potassium carbonate the 9β,11β-oxide compound X isobtained. Reaction of the latter compound with hydrofluoric acid affords2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI, R₁ =R₂ =OCOCH₃) which upon hydrolysis is converted into thecorresponding free alcohol XIa, (XI, N₁ =R₂ =OH). In similar mannerreaction of compound X with hydrochloric acid yields the11-hydroxy-9α-chloro analogue. This reaction with the hydrochloric acidis particularly convenient when R₃ represents methyl.

The fluorine atom at the 6β-position of the compound XI (R₁ =R₂ =OCOCH₃)is considered to be in the stable configuration on the basis of thefollowing observation.

Attempts to isomerize2-bromo-6β,9α-fluoro-11α,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI, R₁ =R₂ =OCOCH₃) with dry hydrochloric acid in chloroform at 0° C.for 2 hrs. do not alter the optical rotatory dispersion curve of thecrude product. Recrystallization affords pure product identical in allaspectes to the starting sample XI (R₁ =R₂ =OCOCH₃).

Reaction of compound X with hydrochloric acid affords2-bromo-6β-fluoro-9α-chloro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-1/,21-diacetate(XIII).

The triene VIII is reacted with N-chlorosuccinimide to obtain the2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XII, R₁ =R₂ =OCOCH₃) which upon hydrolysis is converted into thecorresponding free alcohol XIIa (XII, R₁ =R₂ =OH).

Similarly, the triene VIII can be reacted with N-bromo succinimide toproduce the corresponding 9α,13β dibromo compound XII, especially whenR₃ represents methyl.

When the compound XI (where R₁ =R₂ =OCOCH₃ and R₃ =H) is reacted withpotassium acetate in hot dimethylformamide the2-bromo-6β,9α-difluoro-11β,21-dihydroxypregna-1,4,16-triene-21-acetate(XI bis, R₁ =OCOCH₃)is obtained. The compound XI bis (R₁ =OCOCH₃) isthen oxidized with potassium permanganate to produce the corresponding2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XVII, R₁ =OCOCH₃) which upon hydrolysis is converted into thecorresponding free alcohol XVIIa (XVII, R₁ =OH).

Esterification of the hydroxyl function at the 21-position isconveniently effected with a lower fatty acid anhydride, such as aceticanhydride, or preferably with a lower aliphatic acid chloride such asacetic acid chloride in presence of pyridine, which simultaneouslyserves as solvent.

The 17α-esters are prepared by treatment of the corresonding 17α,21diols with a lower alkyl orthoesters in the presence of an acid catalystfollowed by acid hydrolysis of the resulting 17α,21-orthoester (amixture of two epimeric orthoesters).

The esterification of the hydroxyl function at the 21-position can alsobe achieved by trans-esterification of the corresponding 17α-esters.

Treatment of the corresponding 17α,21-diols with 2,2-dimethoxy-propanein presence of p-toluenesulfonic acid produces the 17,21-acetonides.

Treatment of the compounds XVII with acetone and perchloric acidproduces the 16,17-acetonides XVIII.

The esterification of the hydroxyl function at the 16-position of thecompounds XVII is effected with a lower fatty acid anhydride in presenceof pyridine which simultaneously serves as solvent.

We list below particularly preferred compounds of the invention and forconvenience here and in the Examples denote after the compounds a numbercorresponding to the number of the formula in the figures. In view ofthe large number of subscripts necessary for formula XI we use twosystems of nomenclature. The compounds in which R₃ is hydrogen orhydroxy are numbered by reference to the formulae numbering appearing inFIGS. 1 and 2. The compound in which R₃ is α or β methyl have adifferent system of numbering in which 10 corresponds to formula IX, 11corresponds to formula X and 12 corresponds to formulae XI, XII andXIII.

2,9α-dibromo-6β-fluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(IX)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide(XIb)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XIc)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate(XId)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate(XIe)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate(XIf)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-terbutylacetate(XIg)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enantate(XIh)

2-bromo-β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(XIi)

2-bromo-6β, 9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XIl)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate-21-acetate(XIm)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(XIn)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate-21-valerate(XIo)2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate(XIp)

2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate (XIq)

2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-diene-17,21-diacetate(XII)

2-bromo-6β-fluoro-9α, 11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione (XIIa)

2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-7-acetate(XIIb)

2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XIIc)16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate(12 s)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 t)

16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 u)

16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 v)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12 w)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide(12 z)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate(12 aa)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate(12 ab)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate(12 ac)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydoxy-pregna-1,4-diene-3,20-diene-21-pivalate(12 ad)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(12 ae)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(12 af)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate(12 ag)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate(12 ah)

16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12f)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 h)

16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i)

16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-diene(12 j)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(12 k)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(12 l)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate(12 m)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate(12 n)

16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(12 o)

16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-prena-1,4-diene-3,20-dione-21-acetate(12 p)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 q)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 r)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate(12 s)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 z)

16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 u)

16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 v)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide(12 w)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide(12 z)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate(12 aa)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-diene-21-valerate(12 ab)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate(12 ac)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate(12 ad)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(12 ae)

16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(12 af)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate(12 ag)

16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate(12 ah)

Compounds particularly preferred for topical administration are XI andXId, e, f, i, m, p and q, and compounds 12 k, i and o. Compounds thatare particularly suitable for systemic administration, and also fortopical and systemic administration, are XIa, c and e and XIX and 12 gand k, and XIn is also very useful for systemic administration.

The following are some Examples of the invention:

EXAMPLE 1

A mixture of 8 g. of11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (I), 200 ml. ofbenzene, 80 ml. of ethylene glycol and 4.8 g. of pyridine hydrochloridewas refluxed under stirring for 8 hr. in a water separator. Afterreaction was completed 200 ml. of 5% sodium bicarbonate aqueous solutionwere added. The mixture was further concentrated until crystals appearedand then poured into cold water. The resulting precipitate was removedby filtration, washed neutral with water and dried.

Crystallization of the residue from chloroform and ethyl ether gave 6 g.of11α,17α,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate(II).

IR(KBr) 3565, 3540, 3450 (broad), 1755, 1730, 1220 cm⁻¹

Analysis: Calcd. for C₂₅ H₃₆ O₇ (percent) C 66.94; H8.09. Found(percent) C 67.07; H 8.15.

EXAMPLE 2

A solution of permonophthalic acid (8 g.) in ether (60 ml.) was addedover 1.5 hr. to a solution of 6 g. of11α,17α,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate(II) in chloroform (200 ml.) at -30° C. After keeping at -30° C. for 3hrs. the organic phase was washed acid free with 5% sodium bicarbonateaqueous solution. The solution was then washed with water, dried andevaporated to a residue which by crystallization from methanol gave 4.5g. of11α,17α,21-trihydroxy-3,3-ethylene-dioxy-5α,6α-oxido-pregnane-20-one-21-acetate(III).

IR(KBr) 3585, 3540, 3485 (broad), 1760, 1732, 1230 cm⁻¹

Analysis: Calcd. for C₂₅ H₃₆ O₈ (percent) C 64.63; H 7.81 Found(percent) C 64.78; H 7.82.

EXAMPLE 3

4.5 g. of11α,17α,21-trihydroxy-3,3-ethylene-dioxy-5α,6α-oxido-pregnane-20-one-21-acetate(III) were added over a period of about 1.5 hr. under stirring to 45 ml.of a cooled (-65° C.) 70% hydrofluoric acid aqueous solution. Afteraddition was completed the solution was stirred for 0.5 hr. at -60° C.and then poured into water (650 ml). The solid was dissolved in ethylacetate (400 ml.), the solution was washed with sodium bicarbonateaqueous solution until it was acid free and then washed neutral withwater and finally dried over sodium sulphate. Removal of the solventafforded a crude product M.P. 198°-201° C.

One crystallization from acetone-light petroleum afforded 3 g. of6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV)M.P. 205°-7° C.

[α]_(D) +36° (C 1.0 in dioxane)

λmax (methanol) 290 mμ (ε 104)

IR(KBr) 3640, 3440 (broad), 1745, 1730, 1705, 1230 cm⁻¹.

Analysis: Calcd. for C₂₃ H₃₃ FO₇ (percent) C 62.71; H 7.55; F 4.31.Found (percent) C 62.83; H 7.52; F 4.45.

When the crude product was purified by column chromatography on FLORISIL(Registered Trade Mark) (ratio 1:50) with chloroform-methanol (99:1) aseluant, the6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV)was characterized by M.P. 223°-4° C.

λmax (methanol) 290 mμ (ε 97)

[α]_(D) ²⁰ +51° (C 1.0 in chloroform)

EXAMPLE 4

A mixture of 2 g. of sodium acetate and 10 g. of6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV)dissolved in 100 ml. of dioxane was stirred at 25°-30° C. while asolution of 4 g. of bromine in 50 ml. of dioxane was added dropwise overa period of about 2-3 min. After addition of bromine was completed themixture of reaction was poured into 1500 ml. of a cold 5% sodiumchloride aqueous solution.

After stirring for 1 hour, 8.5 g. of a white crystalline product wascollected by filtration, washed with water and dried.

Crystallization from acetone-methanol-chloroform (1:10:20) gave about 6g. of2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(V) characterized by M.P. 139°-140° C. (decomposition).

[α]_(D) +49° (C 1.0 in dioxane)

λmax (methanol) 288 mμ (ε 124)

IR(KBr) 3530, 3430, 3250 (broad), 1760, 1720, 1220 cm⁻¹.

Analysis: Calcd. for C₂₃ H₃₂ BrFO₇ (percent) C 53.18; H 6.20; Br 15.38;F 3.65. Found (percent) C 52.93; H 6.36; Br 15.59; F 3.44.

EXAMPLE 5

A solution of 10 g. of2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(V) in 50 ml. of pyridine was stirred at -5° C. while dropwise adding 8g. of methane sulfonylchloride over a period of about 15 min. Afteraddition was completed the mixture was stirred for 1.5 hr. maintainingthe temperature at about 0° C., then poured into 400 ml. of cold waterand 200 ml. of dichloroethane. The mixture was acidified at pH 3.5 withan 4N sulphuric acid solution and stirred for 1 hr. The product wascollected by filtration, washed with water and dried giving 9 g. of2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate(VI). Crystallization from benzene gave a white solid characterized by

M.P. 122°-3° C. (decomposition)

[α]_(D) +47° (C 1.0 in dioxane)

λmax (ethanol) 238 mμ (ε 119)

IR(KBr) 3560, 3520 (broad), 1730 (broad) 1330, 1230, 1170 cm⁻¹.

Analysis: Calcd. for C₂₄ H₃₄ BrFO₉ S (percent) C 48.24; H 5.73; Br13.37; F 3.17; S 5.36. Found (percent) C 48.44; H 5.60; Br 13.52; F3.06; S 5.45.

EXAMPLE 6

10 g. of2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate(VI) were added to a solution of 75 ml. of acetic anhydride and 0.5 ml.of 70% perchloric acid in 450 ml. of ethyl acetate.

The mixture was kept at 30° C. for 0.5 hr. and washed successively with5% sodium bicarbonate aqueous solution. The ethyl acetate solution afteranhydrification on sodium sulphate was evaporated to dryness undervacuum.

Crystallization of the residue from methanol gave about 9 g. of2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate(VII) characterized by

M.P. 131°-2° C. (decomposition)

[α]_(D) -11.7° (C 1.0 in chloroform)

λmax (methanol) 285 mμ (ε 104)

IR(KBr) 1740 (broad), 1370, 1230 (broad), 1170 cm⁻¹

NRM (CDCl₃ -TMS) Hz at 60 MHz 355, 307 (doublet of triplets, 1,C-6 H)304-290 m, 2, C-2H and C-11 H) 300, 284, 278, 262 (doublet of doublets,2, --CH₂ OAc) 224, 210 (J, 1, C-4 Hα) 184 (S, 3, OSO₂ CH₃) 124 (S, o,2OAc) 120 (S, 3, OAc) 94,90 (d, 3, 19 CH₃ split by 6βF) 48 (S, 3, 18CH₃)

Analysis: Calcd. for C₂₈ H₃₈ BrFO₁₁ S (percent) C 49.34; H 5.62; Br11.72; F 2.79; S 4.70 Found (percent) C 49.13; H 5.43; Br 12.03; F 2.65;S 4.57.

EXAMPLE 7

6.8 g. of2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate(VII) were dissolved in 330 ml. of anhydrous acetic acid at 90° C. onthe steam-bath. A solution of sodium acetate (15.3 g. dried at 100° C.)in acetic acid (60 ml.) at 90° C. was added, followed immediately by1.75 g. of bromine in acetic acid (25 ml.), added in one lot. Heating at90° C. was continued until the bromine colour disappeared (about 3 min.in all). The solution was then cooled as rapidly as possible to roomtemperature and poured in cold water. The solid was collected byfiltration, washed thoroughly with water and dried to a constant weight,giving about 6.5 g. of VIIbis(2,2-dibromo-6β-fluoro-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate).Crystallization from methanol gave a white solid characterized by

M.P. 140°-2° C. (decomposition)

λmax (methanol) 242-3 mμ (ε 10000)

IR(KBr) 1745, 1730, 1697, 1625, 1340, 1230, 1170 cm⁻¹

[α]_(D) -18 (C 1.0 in chloroform)

NMR (CDCl₃ -TMS) Hz at 60 mHz 362,358 (d, 1, C-4H) 328,278 (doublet oftriplets, 1, C-6 H) 320-290 (m, 1, C-11 H) 302,286,280,264 (doublet ofdoublets, 2, --CH₂ OAc) 228,212,204,188 (doublet of doublets, 2, C-1H.sub.α and H.sub.β) 190 (S, 3,--OSO₂ CH₃) 130 (S, 3, OAc) 128 (S, 3,OAc) 108,104 (d, 3, 19 CH₃ split by 6βF) 52 (S, 3, 18 CH₃)

Analysis: Calcd. for C₂₆ H₃₃ Br₂ FO₉ S (percent) C 44.58; H 4.75; Br22.82; F 2.71; S 4.58. Found (percent) C 44.63; H 4.81; Br 22.69; F2.84; S 4.38.

EXAMPLE 8

7 g. of2,2-dibromo-6β-fluoro-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate(VII bis) were added, in one portion, to a mixture of 70 ml. ofdimethylformamide, 14 g. of lithium carbonate and 7 g. of lithiumbromide under stirring at 100° C. The reaction mixture was then refluxedat 130° C. under nitrogen for 0.5 hr., cooled and poured into coldwater. The precipitate was filtered off, washed with water and dried.

Crystallization of the residue from acetone gave 4.8 g. of2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(VIII) characterized by M.P. 270°-1° C. (decomposition)

[α]_(D) -88,5° (C 1.0 in chloroform)

λmax (methanol) 246-7 mμ (ε 12750)

IR(KBr) 1740 (broad), 1675, 1645, 1600, 1230 cm⁻¹.

NMR (CDCl₃ - TMS) Hz at 60 mHz 452 (S, 1, C-1 H) 376,372 (d, 1, C-4 H)342-332 (m, 1, C-11 H) 334,286 (doublet of triplets, 1, C-6 H)302,284,280,262 (doublet of doublets, 2, CH₂ OAc) 130 (S, 3, OAc) 123(S, 3, OAc) 94,92 (d, 3, 19 CH₃ split by 6βF) 45 (S, 3, 18 CH₃).

Analysis: Calcd. for C₂₅ H₂₅ BrFO₆ (percent) C 57.37; H 5.39; Br 15.27;F 3.63. Found (percent) C 57.53; H 5.61; Br 15.03; F 3.71.

EXAMPLE 9

7.1 g. of 1,3-dibromo-5,5-dimethyl-hydantoin were added in the dark atroom temperature under stirring over a period of 0.5 hr. to a suspensionof 10 g. of2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(VIII) in 200 ml. of tetrahydrofurane and 1 g. of 70% perchloric acid in10 ml. of water. During the addition the suspension began to thin andafter a total reaction time of 45 min. all the starting material wasdissolved. After an additional 2 hrs., 10% sodium sulfite aqueoussolution was added under stirring until KJ-starch paper was no longerblued. The solution was slowly poured into 1000 ml. cold water. Theproduct (IX) was filtered and utilized moist in the next reaction.Analytically pure2,9α-dibromo-6β-fluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(IX) was obtained by additional crystallization from acetone-hexane. Itwas dried in vacuo at room temperature M.P. 208°-10° C. (decomposition)

[α]_(D) -18,2° (C 1.0 in chloroform)

λmax (methanol) 248 mμ (ε 10250)

IR(KBr) 3520, 1755, 1740, 1710, 1675, 1640, 1605, 1230 cm⁻¹.

Analysis: Calcd. for C₂₅ H₂₉ Br₂ FO₇ (percent) C 48.41; H 4.71; Br25.70; F 3.06 Found (percent) C 48.74; H 4.65; Br 25.60; F 3.31.

EXAMPLE 10

40 ml. of a 14% potassium carbonate aqueous solution were added over aperiod of 20 min. at 20° C. under stirring to the solution of the moistproduct (IX)2,9α-dibromo-6β-fluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(obtained in Example 9 from 10 g. of the product VIII) in 200 ml. ofacetone. The solution was stirred for 4 hr. Ice water was addedunderstirring, upon which crystallizaton occurs rapidly. The product2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11β-oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate(X) was filtered, washed with water, dried and characterized by M.P.241°-2° C. (decomposition), raised by crystallization frombenzene-cyclohexane to 248°-9° C.

[α]_(D) -88.4° (C 0.5 in chloroform)

IR(KBr) 1755, 1740 (broad), 1670, 1640, 1600, 1230 (broad) cm⁻¹.

Analysis: Calcd. for C₂₅ H₂₈ BrFO₇ (percent) C 55.67; H 5.23; Br 14.81;F 3.52. Found (percent) C 55.80; H 5.15; Br 14.72; F 3.45.

EXAMPLE 11

100 ml. of a 70% hydrofluoric acid aqueous solution were cooled to -10°C. in a polyethylene flask equipped with electromagnetic stirrer. 10 g.of2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11β-oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate(X) were added under stirring during 15 min. After 0.5 hr. the reactionmixture was precipitated in water and ammonia. The solid was collectedby filtration, washed with water and dried to a constant weight, givingabout 9.5 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI) (R₁ =R₂ =OCOCH₃).

Crystallization from benzene gave 7 g. of pure product, homogeneous byTLC on silica gel (6:3:2 CHCl₃ -acetone-cyclohexane).

M.P. 290°-2° C. (decomposition)

[α]_(D) -36° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 12500)

IR(KBr) 3520, 1758, 1733, 1705, 1680, 1650, 1610, 1235 cm⁻¹.

NMR (dimethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 471 (S,1,C-1 H) 393,389(d,1,C-4H) 350,300 (doublet of triplets,1,C-6H) 341,335 (d,1,C-110H) 289(S,2,CH₂ OAc)270-240(m,1,C-11H) 127 (S,3,OAc) 122 (S,3,OAc) 99.96 (d,3,19 CH₃ split by 6βF) 56 (S,3, 18 CH₃).

M.S. (70 e.v., ion source temperature 210° C., direct sampleintroduction) ions at m/e 558/560 (M+, C₂₅ H₂₉ BrF₂ O₇), 540/542,538/540, 518/520, 498/500, 483/485, 478/480, 458/460, 397/399, 377/379,359/361, 357/359, 339/341, 317/319, 315/317, 299/301, 278, 217/219,212/214, 199/201, 165, 147, 139, 121, 109, 101, 91, 79, 73 (base peak),69, 60, 55.

Analysis: Calcd. for C₂₅ H₂₉ BrF₂ O₇ (percent) C 53.67; H 5.22; F 6.79;Br 14.28. Found (percent) C 53.27; H 5.22; F 6.80; Br 14.32.

EXAMPLE 12

A suspension of 10 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI) (R₁ =R₂ =OCOCH₃) in 200 ml. of 1% potassium hydroxide methanolicsolution was stirred under nitrogen at 0° C. for 3 hrs.

Addition of cold water, elimination of methanol in vacuo, acidificationwith acetic acid and filtration gave 7 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI;R₁ =R₂ =OH).

M.P. 223°-227° C. (decomposition), raised by crystallization fromdichloroethane to 228°-230° C.

[α]_(D) -5.6° (C 1.0 in dioxane)

λmax (methanol) 246 mμ (ε 11700)

IR(KBr) 3430 (broad), 1715, 1670, 1645, 1600 cm⁻¹.

NMR (dimethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 470(S,1,C-1H) 392,388(d,1,C-4H) 348,298 (doublet of triplets,1,C-6H) 327,322(d,1,C-11 OH)316(S,1,C-17OH) 280,276,270,266,261,257,250,246(octuplet which becomes aquartet bu deuterium exchange,2,COCH₂ OH) 99,96(d,3,19 CH₃ split by 6βF)48 (S,3,18 CH₃).

M.S. (70 e.v., ion source temperature 210° C., direct sampleintroduction) ions at m/e 474/476 (M+, C₂₁ H₂₅ BrF₂ O₅) 456/458,444/446, 427/429, 414/416, 394/396, 379/381, 359/361, 317/319, 315/317,219/221, 217/219 (base peak), 212/214, 199/201, 139, 109, 95, 67, 55.

Analysis: Calcd. for C₂₁ H₂₅ BrF₂ O₅ (percent) C 53.06; H 5.30; Br16.81; F 7.99 Found (percent) C 53.15; H 5.30; Br 16.73; F 8.05.

EXAMPLE 13

To a solution of 10 g. of2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(VIII) and 40 g. lithium chloride in 200 ml. of glacial acetic acid wereadded at 20° C. under stirring 5 g. of N-chlorosuccinimide. The mixturewas kept at 20° C. and stirred while dropwise adding 10 ml. of a 12%hydrochloric acid tetrahydrofurane solution over a period of about 10min. After 3.5 hrs. the reaction mixture was poured into cold water, thesolid collected by filtration, washed with water and dried, giving 6 g.of pure product2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate

(XII) (R₁ =R₂ =OCOCH₃). M.P. 244°-6° C. (decomp.) [α]_(D) -2.5° (C 1.0in chloroform)

IR(KBr) 1753, 1740, 1672, 1645, 1602, 1230 cm⁻¹.

NMR (dimethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 465 (S,1,C-1H) 394,390(d,1,C-4H) 350,300 (doublet of triplets, 1,C-6H) 320-305 (m,1,C-11H) 289(S,2,CH₂ OAc) 127 (S,3,OAc) 122 (S,3,OAc) 110, 106 (d,3, 19 CH₃ split by6βF) 61 (S,3, 18 CH₃).

Analysis: Calcd. for C₂₅ H₂₈ BrCl₂ FO₆ (percent) C 50.27; H 4.72; F3.18; Cl 11.87; Br 13.38. Found (percent) C 50.55; H 4.81; F 3.25; Cl12.05; Br 13.67.

λmax (methanol) 245-6 mμ (ε 12280)

EXAMPLE 14

Using the general procedure of Example 12 the2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XII) (R₁ =R₂ =OCOCH₃) was converted to2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dioneXIIa (XII, R₁ =R₂ =OH)

M.P. 185°-7° C. (decomposition)

λmax (methanol) 245 (ε 12000)

[α]_(D) +34° (C 0.7 in chloroform)

IR(KBr) 3450 (broad), 1715, 1675, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₁ H₂₄ BrCl₂ FO₄ (percent) C 49.43; H 4.74; F3.72; Cl 13.90; Br 15.66. Found (percent) C 49.78; F 3.70; Cl 14.07; Br15.75; H 4.76.

EXAMPLE 15

A mixture of 7 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI)(R₁ =R₂ =OCOCH₃), 70 ml. of dimethylformamide and 3.5 g. of anhydrouspotassium acetate was refluxed at 120° C. under nitrogen for 0.5 hr. Thereaction mixture was then cooled and poured into cold water. Theprecipitate was filtered off, washed with water, dried.

Crystallization of the residue from acetone-hexane gave 5 g. of2-bromo-0β,9α-difluoro-11β,21-dihydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate(XIbis) (R₁ =OCOCH₃) characterized by M.P. 257°-8° C. (decomposition).

[α]_(D) +24° (C 1.0 in chloroform)

IR(KBr) 3520, 1730, 1680, 1640, 1600, 1588, 1220 cm⁻¹.

λmax (methanol 242-3 mμ (ε 21500)

Analysis Calcd. for C₂₃ H₂₅ BrF₂ O₅ (percent) C 55.32; H 5.04; Br 16.00;F 7.61. Found (percent) C 55.21; H 4.89; Br 16.25; F 7.49.

EXAMPLE 16

A solution of potassium permanganate (3.5 g.) in acetone (75 ml.) andwater (25 ml.) was added, in one portion, at -5° C. to a solution of 5g. of2-bromo-6β,9α-difluoro-11β,21-dihydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate(XIbis) (R₁ =OCOCH₃) in acetone (150 ml.) and formic acid (1.7 ml.).

The mixture of reaction was stirred for 5 min. at -5° C. and then 50 ml.of 10% Na₂ SO₃ aqueous solution were added. The mixture was filteredthrough Celite (Trade Mark) and the pale yellow filtrate concentrated invacuo and poured into cold water.

The solid filtered after crystallization from acetone-hexane yielded 4.5g. of2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XVII) (R₁ =OCOCH₃) characterized by M.P. 225°-7° C. (decomposition)

[α]_(D) -16° (C 1.0 in dioxane)

λmax (methanol) 245-6 mμ (ε 12000)

IR(KBr) 3440 (broad), 1745, 1732, 1672, 1645, 1605, 1230 cm⁻¹. NMR(Jimethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 472 (S,1,C-1H) 392,388(d,1,C-4H) 348,298 (doublet of triplets,1,C-6H) 337,332 (d,1,C-11 OH)328,323 (d,1,C-16 OH) 312,296,292,276(doublet and doublets, 2,CH₂ OAc)290 (S,1,C-17 OH) 290-280 (m,1,C-16 H) 265-240 (m,1,-11 H) 126 (S,3,OAc)98,95 (d,3,19 CH₃ split by 6βF) 52 (S3,18 CH₃).

Analysis: Calcd. for C₂₃ H₂₇ BrF₂ O₇ (percent) C 51.79; H 5.10; F 7.12;B 14.98. Found (percent) C 52.05; H 5.02; F 7.25; Br 16.18.

EXAMPLE 17

Using the general procedure of Example 12 the2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XVII) (R₁ =OCOCH₃) was converted to2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione(XVIIa) (XVII R₁ =OH). M.P. 208°-10° C. (decomposition)

IR(KBr) 3460 (broad), 1715, 1670, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₁ H₂₅ BrF₂ O₆ (percent) C 51.33; H 5.13; Br16.26; F 7.37. Found (percent) C 51.51; H 5.10; Br 16.15; F 7.81.

[α]_(D) -30° (C 1.0 in dioxane)

λmax (methanol) 246-7 m μ (ε 11400)

EXAMPLE 18

A solution of 5 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI, R₁ =R₂ =OH) in 10 ml. of dimethylformamide and 37 ml. of2,2-dimethoxypropane with 0.025 g. of p-toluenesulfonic acid was heatedfor 6 hrs. at 115° C.

The reaction mixture was cooled, poured in 10% sodium bicarbonateaqueous solution and chloroform. The chloroform solution was then washedwith water, dried and evaporated to a residue which by crystallizationfrom acetone gave 4 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide(XIb) characterized by M.P. 230°-1° C. (decomposition)

[α]_(D) -1° (C 1.0 in chloroform)

λmax (methanol) 245-6 (ε 12100)

IR(KBr) 3440 (broad), 1720, 1670, 1645, 1600 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₅ (percent) C 55.93; H 5.67; Br15.50; F 7.37. Found (percent) C 56.07; H 5.72; Br 15.37; F 7.50.

EXAMPLE 19

2.5 ml. of 70% perchloric acid were added under stirring at 15° C. to asuspension of 10 g. of2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XVII) (R₁ =OCOCH₃) in 400 ml. of acetone. The solution was stirred at15° C. for 50 min. and 5 g. of sodium bicarbonate were added.

The mixture was stirred for 10 min. and then filtered. The acetonesolution was evaporated to dryness in vacuo at 60° C. The solid residuewas crystallized from ethylacetate-light petroleum giving 6 g. of pure2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate-16,17-acetonide(XIX) (R₁ =OCOCH₃, R₄ =R₅ =CH₃) IR(KBr)3560,3480,3430,1755,1730,1670,1645,1600,1225 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₁ BrF₂ O₇ (percent) C 54.46; H 5.45; Br13.93; F 6.62. Found (percent) C 54.65; H 5.57; Br 13.85; F 6.47.

[α]_(D) +8° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11550)

EXAMPLE 20

5 ml. of acetic anhydride were dropwise added to a mixture of 50 ml. ofpyridine and 10 g. of2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XVII) (R₁ =OCOCH₃). The mixture was kept at room temperature for 1.5hr. and then poured under vigorous stirring into 500 ml. of cold water.After about 0.5 hr. the solid was collected by filtration, washedthoroughly with cold water, dried to a constant weight, giving about 9.5g. of2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,21-diacetate(XVII) (R₁ =R₃ =OCOCH₃), crystallized by methanol-water. IR(KBr)3570,3500 (broad), 1760,1735 (broad) 1670,1645,1605,1240 (broad) cm⁻¹.

Analysis: Calcd. for C₂₅ H₂₉ BrF₂ O₈ (percent) C 52.18; H 5.08; Br13.89; F 6.60. Found (percent) C 52.07; H 5.10; Br 14.07; F 6.70.

M.P. 238°-40° C. (decomposition)

[α]_(D) -49.4° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11900)

EXAMPLE 21

5 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH) were dissolved in 50 ml. of pyrid ine containing25 ml. of acetic anhydride and kept at room temperature for 12 hrs.Addition of ice water afforded a product which was extracted withchloroform. The chloroform solution was washed with water, 2N HCl, 5%sodium bicarbonate solution and water. After drying (Na₂ SO₄) andremoval of the solvent in vacuo the residue was crystallized fromacetone-hexane to gave2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-21-acetate(XIc) (XI,R₁ =OCOCH₃, R₂ =OH) characterized by M.P. 194°-6° C.(decomposition).

[α]_(D) +12° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11800)

IR(CHCl₃) 3620, 3500 (broad), 1745, 1730, 1672, 1645, 1605, 1230 (broad)cm⁻¹.

Analysis: Calcd. for C₂₃ H₂₇ BrF₂ O₆ (percent) C 53.39; H 5.26; Br15.44; F 7.34. Found (percent) C 53.51; H 5.21; Br 15.70; F 7.28.

EXAMPLE 22

Using the general procedure of Example 21, the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate(XId) (XI,R₁ =OCOCH₂ CH₃, R₂ =OH) by reaction with propionic anhydride.

M.P. 180°-3° C. (decomposition)

[α]_(D) +22° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 10900)

IR(CHCl₃) 3610, 3500 (broad), 1740, 1728, 1672, 1645, 1605, 1220 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₆ (percent) C 54.25; H 5.50; Br15.04; F 7.15. Found (percent) C 54.09; H 5.60; Br 14.92; F 7.05.

EXAMPLE 23

Using the general procedure of Example 21, the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate(XIe) (XI,R₁ =OCO(CH₂)₃ CH₃, R₂ =OH) by reaction with valeric anhydride.

M.P. 155°-7° C. (decomposition)

[α]_(D) +27° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11600)

IR(KBr) 3500 (broad), 1740, 1720, 1670, 1640, 1600, 1230 (broad) cm⁻.

Analysis: Calcd. for C₂₆ H₃₃ BrF₂ O₆ (percent) C 55.82; H 5.94; Br14.28; F 6.79. Found (percent) C 55.70; H 5.91; Br 14.35; F 6.87.

EXAMPLE 24

Using the general procedure of Example 21, the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate(XIf) (XI,R₁ =OCOC(CH₃)₃,R₂ =OH) by reaction with pivalic anhydride.

M.P. 224°-6° C. (decomposition)

[α]_(D) +22° (C 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε 10900)

IR(KBr) 3470 (broad), 1740, 1730, 1665, 1640, 1600, 1220 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₃ BrF₂ O₆ (percent) C 55.82; H 5.94; Br14.28; F 6.79. Found (percent) C 55.75; H 5.88; Br 14.07; F 6.65.

EXAMPLE 25

3 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH) were dissolved in 30 ml. of pyridine containing 1ml. of terbutylacetic acid chloride and kept at room temperature for 16hours.

Addition of ice water afforded a product which was extraced withchloroform. The chloroform solution was washed with 5% sodiumbicarbonate solution and water. After drying (Na₂ SO₄) and removal ofthe solvent in vacuo, the residue was crystallized from acetone-hexaneto give2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-terbutylacetateXIg) (XI,R₁ =OCOCH₂ C(CH₃)₃,R₂ =OH).

M.P. 198°-200° C. (decomposition)

[α]_(D) +25° (C 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε 10900)

IR(KBr) 3490 (broad), 1735 (broad), 1670, 1640, 1600, 1230 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₅ BrF₂ O₆ (percent) C 56.55; H 6.15; Br13.93; F 6.62. Found (percent) C 56.71; H 6.02; Br 18.85; F 6.75.

EXAMPLE 26

Using the general procedure of Example 25 the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-enantate(XIh) (XI,R₁ =OCO(CH₂)₅ CH₃,R₂ =OH) by reaction with enanthic acidchloride.

M.P. 173°-5° C. (decomposition)

[α]_(D) +28° (C 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε 11500)

IR(KBr) 3500 (broad), 1735 (broad), 1670, 1640, 1600, 1230 (broad) cm⁻¹.

Analysis: Calcd. for C₂₈ H₃₇ BrF₂ O₆ (percent) C 57.24; H 6.35; Br13.60; F 6.47. Found (percent) C 57.31; H 6.30; Br 13.72; F 6.29.

EXAMPLE 27

Using the general procedure of Example 21 the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(XIi) (XI,R₁ =OCOC₆ H₅,R₂ =OH) by reaction with benzoic anhydride.

M.P. 209°-10° C. (decomposition)

[α]_(D) +93° (C 1.0 in chloroform)

λmax (methanol) 233-4 mμ (ε 22000)

IR(KBr) 3600, 3420 (broad), 1725, 1710, 1670, 1640, 1600 cm⁻¹.

Analysis: Calcd. for C₂₈ H₂₉ BrF₂ O₆ (percent) C 58.04; H 5.04; Br13.79; F 6.56. Found (percent) C 58.21; H 4.93; Br 13.68; F 6.39.

EXAMPLE 28

A mixture of 5 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa) (XI,R₁ =R₂ =OH), 5 ml. of methylorthovalerate and 0.020 g. ofp-toluene sulfonic acid in 15 ml. of dimethylformamide was maintainedfor 4 hrs. under nitrogen at 115° C.

Then the mixture was neutralized by pyridine and concentrated undervacuum to dryness. Purification by column chromatography on FLORISIL(Registered Trade Mark) (ratio 1:30) with benzene-chloroform (8:2) aseluent, gave 3.5 g. of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-(1'-methoxy)-n-pentylidenedioxy,which without further purification was suspended in 25 ml. of methanoland 3 ml. 1N hydrochloric acid aqueous solution, heated on water bath at40°-50° C.

After complete solubilization of the product, the mixture wasconcentrated under vacuum.

The insoluble product was filtered off, washed with water and thendried. The2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate(XI1) (XI,R₁ =OH,R₂ =OCO(CH₂)₃ CH₃) thus obtained was crystallized fromacetone-hexane and characterized by

M.P. 201°-3° C. (decomposition)

[α]_(D) -74° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 12600)

IR(KBr) 3500 (broad), 1730, 1715, 1670, 1645, 1600 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₃ BrF₂ O₆ (percent) C 55.82; H 5.94; Br14.28; F 6.79. Found (percent) C 55.91; H 6.07; Br 14.27; F 6.72.

EXAMPLE 29

Using the general procedure of Example 21 the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate(XI 1) (XI,R₁ =OH,R₂ =OCO(CH₂)₃ CH₃) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate-21-acetate(XI m) (XI,R₁ =OCOCH₃,R₂ =O(CH₂)₃ CH₃) by reaction with aceticanhydride. The product was crystallized from acetone-hexane. Thecrystals showed at 125° C. a transaction from the low melting form II tothe form I melting 173°-5° C. (decomposition).

[α]_(D) -25° (C 1.0 in chloroform)

λmax (methanol 245-6 mμ (ε 11400)

IR(KBr) 3500 (broad), 1735 (broad), 1672, 1645, 1230 (broad) cm⁻¹.

Analysis: Calcd. for C₂₈ H₃₅ BrF₂ O₇ (percent) C 55.91; H 5.86; Br13.28; F 6.32. Found (percent) C 56.03; H 5.91; Br 13.07; F 6.28.

EXAMPLE 30

Using the general procedure of Example 28 the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa)(XI, R₁ =R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydoxy-pregna-1,4-diene-3,20-dione-17-acetate(XI n) (XI,R₁ =OH, R₂ =OCOCH₃) by reaction with ethylorthoacetatefollowed by acid hydrolysis of the resulting 17,21-orthoacetate. Theproduct was crystallized from acetone-hexane.

M.P. 230°-2° C. (decomposition)

[α]_(D) -75.8° (C 1.0 in chloroform)

λmax (methanol) 245 mμ (ε 11700)

IR(KBr) 3500, 3420, 1730, 1720, 1675, 1640, 1610, 1220 cm⁻¹.

Analysis: Calcd. for C₂₃ H₂₇ BrF₂ O₆ (percent) C 53.40; H 5.26; Br15.44; F 7.34. Found (percent) C 53.52; H 5.32; Br 15.52; F 7.27.

EXAMPLE 31

Using the general procedure of Example 21 the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(XI m) (XI,R₁ =OH,R₂ =OCOCH₃) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate-21-valerate(XI o) (XI, R₁ =OCO(CH₂)₃, R₂ =OCOCH₃) by reaction with valericanhydride. The product was crystallized from acetone-hexane.

M.P. 159°-60° C. (decomposition)

[α]_(D) -37° (C 1.0 in chloroform)

λmax (methanol) 246-7 mμ (ε 11750)

IR(KBr) 3660, 3520, 3380, 1730 (broad), 1675, 1640, 1600, 1240 cm⁻¹.

Analysis: Calcd. for C₂₈ H₃₅ BrF₂ O₇ (percent) C 55.91; H 5.86; Br13.28; F 6.32. Found (percent) C 56.07; H 5.73; Br 13.21; F 6.55.

EXAMPLE 32

Using the general procedure of Example 28 the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa)(XI,R₁ =R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate(XI p) (XI,R₁ =OH,R₂ =OCOCH₂ CH₃) by reaction with ethylorthopropionatefollowed by acid hydrolysis of the resulting 17,21-orthopropionate.

The product was crystallized by acetone-hexane:

M.P. 215°-7° C. (decomposition)

λmax (methanol) 245-6 mμ (ε 12300)

[α]_(D) -75° (C 1.0 in chloroform)

IR(KBr) 3500, 3420, 1730, 1712, 1675, 1640, 1605, 1200 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₆ (percent) C 54.24; H 5.50; Br15.04; F 7.15. Found (percent) C 54.20; H 5.52; Br 14.79; F 6.97.

EXAMPLE 33

Using the general procedure of Example 28 the2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa)(XI,R₁=R₂ =OH) was converted to2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate(XI q) (XI,R₁ =OH, R₂ =OCOC₆ H₅) by reaction with ethylorthobenzoatefollowed by acid hydrolysis of the resulting 17,21-orthobenzoate. Theproduct was crystallized by acetone-hexane.

M.P. 241°-3° C. (decomposition)

[α]_(D) -103° (C 1.0 in chloroform)

λmax (methanol) 234-5 mμ (ε 23500)

IR(KBr) 3520, 3430, 1730, 1700, 1680, 1645, 1610 cm⁻¹.

Analysis: Calcd. for C₂₈ H₂₉ BrF₂ O₆ (percent) C 58.04; H 5.04; Br13.79; F 6.56. Found (percent) C 58.12; H 4.95; Br 13.62; F 6.50.

EXAMPLE 34

Using the general procedure of Example 28 the2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione(XIIa) (XII,R₁ =R₂ =OH) was converted to2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(XIIb) (XII,R₁ =OH, R₂ =OCOCH₃) by reaction with ethylorthoacetatefollowed by acid hydrolysis of the resulting 17,21-orthoacetate. Theproduct was crystallized by acetone-hexane.

M.P. 193°-4° C. (decomposition)

[α]_(D) -32° (C 1.0 in chloroform)

λmax (methanol) 245 mμ (ε 11700)

IR(KBr) 3500, 1730 (broad), 1705, 1680, 1650, 1605, 1240 (broad) cm⁻¹.

Analysis: Calcd. for C₂₃ H₂₆ BrCl₂ FO₅ (percent) C 50.02; H 4.74; Br14.47; Cl 12.84; F 3.44. Found (percent) C 50.11; H 4.82; Br 14.35; Cl13.03; F 3.32.

EXAMPLE 35

Using the general procedure of Example 21 the2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione(XIIa) (XII,R₁ =R₂ =OH) was converted to2-bromo-6β-fluoro-9α,11β-dicloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XII c) (XII,R₁ =OCOCH₃, R₂ =OH) by reaction with acetic anhydride. Theproduct was crystallized from benzene-light petroleum.

M.P. 202°-4° C. (decomposition)

[α]_(D) +49° (C 1.0 in chloroform)

λmax (methanol) 245 mμ (ε 11800)

IR(KBr) 3470, 1750, 1730, 1668, 1640, 1600, 1230 cm⁻¹.

Analysis: Calcd. for C₂₃ H₂₆ FCl₂ BrO₅ (percent) C 50.02; H 4.74; Br14.47; Cl 12.84; F 3.44. Found (percent) C 50.21; H 4.63; Br 14.41; Cl12.79; F 3.38.

EXAMPLE 36

Using the general procedure of example 19 the2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione(XVIIa) (XVII, R₁ =OH) was converted into2-bromo-6β,9α-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide(XIXa) (XIX, R₁ =OH, R₄ =R₅ =CH₃) crystallized from acetone-hexane.

M.P. 221°-3° C. (decomposition)

[α]_(D) ²⁰ +9 (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11950)

IR(KBr) 3500, 3280, 1730, 1670, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₆ (percent) C 54.25; H 5.50; Br15.04; F 7.15. Found (percent) C 54.37; H 5.42; Br 14.95; F 7.10.

EXAMPLE 37

50 ml. of hydrochloric acid were added at 0° C. over a period of 30 min.to a suspension of 5 g. of2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11β-oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate(X) in 30 ml. of acetone.

The mixture was held at 0° C. under stirring for 6 hrs. and then theprecipitated2-bromo-6βfluoro-9α-chloro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XXIII) was recovered by filtration, washed repeatedly with water, driedand crystallized by acetone-hexane.

M.P. 258°-60° C. (decomposition)

[α]_(D) ²⁰ -22° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11100)

IR(KBr) 3440 (broad), 3350, 1753, 1740, 1705, 1675, 1645, 1600, 1230cm⁻¹.

Analysis: Calcd. for C₂₅ H₂₉ BrClFO₇ (percent) C 52.14; H 5.08; Br13.88; Cl 6.16; F 3.30. Found (percent) C 52.34; H 5.02; Br 13.72; Cl6.22; F 3.25.

EXAMPLE 38

A mixture of 4.1 g. of16α-methyl-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (1 a)(R₃ =αCH₃), 110 ml. of benzene, 41 ml. of ethylene glycol and 2.45 g. ofpyridine hydrochloride was refluxed under stirring for 8 hrs. in a waterseparator. After the reaction was completed 100 ml. of 5% sodiumbicarbonate aqueous solution were added. The mixture was furtherconcentrated until crystals appeared and then poured into cold water.The resulting precipitate was removed by filtration, washed neutral withwater and dried.

Crystallization of the residue gave 3.7 g. of16α-methyl-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate(2 a) (R₃ =αCH₃) characterized by

M.P. 214°-6° C.

λmax (methanol) 292 mμ (ε 110)

[α]_(D) ²⁰ +1° (C 1.0 in chloroform)

IR(KBr) 3480 (broad), 1755,1730,1230 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₈ O₇ (percent) C 67.51; H8.28 Found (percent)C 67.68; H 8.35.

EXAMPLE 39

Using the general procedure of example 38 the16β-methyl-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (1 b)(R₃ =βCH₃) was converted into16β-methyl-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate(II b)(R₃ =βCH₃) characterized by

M.P. 214°-6° C.

λmax (methanol) 292 mμ (ε 130)

[α]_(D) ²⁰ +36 (C 1.0 in chloroform)

IR(KBr) 3525 (broad), 1755, 1730, 1230 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₈ O₇ (percent) C 67.51; H 8.28 Found(percent) C 67.57; H 8.15.

EXAMPLE 40

A solution of monoperphthalic acid (21 g.) in ether (120 ml.) was addedover 1.5 hr. to a solution of 15 g. of16α-methyl-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate(II a) (R₃ =αCH₃) in chloroform (500 ml.) at -30° C. After keeping at-30° C. for 3 hrs. the organic phase was washed acid free with 5% sodiumbicarbonate aqueous solution. The solution was then washed with water,dried and evaporated to a residue which by crystallization from methanolgave 12 g. of16α-methyl-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-5.alpha.,6α-oxido-pregnane-20-one-21-acetate(III a)(R₃ =αCH₃) characterized by

IR(KBr) 3600, 3520, 1755, 1725, 1235 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₈ O₈ (percent) C 65.25; H 8.00 Found(percent) C 65.20; H 7.92.

EXAMPLE 41

Using the general procedure of example 40 the 16β-methyl-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-pregn-5-ene-20-one-21-acetate (II b)(R₃ =βCH₃) was converted into16β-methyl-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-5.alpha.,6α-oxido-pregnane-20-one-21-acetate(III b)(R₃ =βCH₃) characterized by

IR(KBr) 3550, 3450 (broad), 1740, 1728, 1235 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₈ O₈ (percent) C 65.25; H 8.00 Found(percent) C 65.37; H 8.08.

EXAMPLE 42

4.5 g. of 16α-CH₃-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-5α,6α-oxido-pregnane-20-one-21-acetate(III a)(R₃ =αCH₃) were added over a period of about 1.5 hr. understirring to 45 ml. of a cooled (-65° C.) 70% hydrofluoric acid aqueoussolution. After addition was completed the solution was stirred for 0.5hr. at -60° C. and then poured into water (650 ml.). The solid wasdissolved in ethyl acetate (400 ml.), the solution was washed withsodium bicarbonate aqueous solution until it was acid free and thenwashed neutral with water and finally dried over sodium sulphate.Removal of the solvent afforded a crude product which by onecrystallization from acetone-hexane afforded 3.2 g. of16α-methyl-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(IV a)(R₃ =αCH₃) characterized by

M.P. 218°-20° C.

λmax (methanol) 290 mμ (ε 90)

[α]_(D) ²⁰ +21° (C 1.0 in chloroform)

IR(KBr) 3640, 3560, 3450 (broad), 1740,1730,1710,1230 cm⁻¹.

Analysis: Calcd. for C₂₄ H₃₅ FO₇ (percent) C 63.42; H 7.76; F 4.18 Found(percent) C 63.50; H 7.65; F 4.15.

EXAMPLE 43

Using the general procedure of example V the16β-methyl-11α,17α,21-trihydroxy-3,3-ethylene-dioxy-5.alpha.,6α-oxido-pregnane-20-one-21-acetate(III b)(R₃ =βCH₃) was converted into16β-methyl-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(4 b)(R₃ =βCH₃)

M.P. 220°-2° C.

[α]_(D) ²⁰ +54° (C 1.0 in chloroform)

λmax (methanol) 292 mμ (ε 98)

IR(KBr) 3640, 3460 (broad), 1750,1730,1705,1235 cm⁻¹.

Analysis: Calcd. for C₂₄ H₃₅ FO₇ (percent) C 63.42; H 7.76; F 4.18 Found(percent) C 63.31; H 7.62; F 4.02.

EXAMPLE 44

A mixture of 2 g. of sodium acetate and 10 g. of16α-methyl-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(IVa)(R₃ =αCH₃) dissolved in 100 ml. of dioxane was stirred at 25°-30°C. while a solution of 4 g. of bromine in 50 ml. of dioxane was addeddropwise over a period of about 2-3 min. After addition of bromine wascompleted the mixture of reaction was poured into 1500 ml. of a cold 5%sodium chloride aqueous solution. After stirring for 1 hr., a whitecrystalline product was collected by filtration, washed with water anddried,16α-methyl-2α-bromo-6β-fluoro-5α,11α,17.alpha.,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(V a)(R₃ =αCH₃). Crystallization from acetone-hexane gave about 7 g. ofwhite solid characterized by

M.P. 137°-8° C. (decomposition)

[α]_(D) ²⁰ +27° (C 1.0 in dioxane)

λmax (methanol) 288 mμ (ε 112)

IR(KBr) 3640,3560,3470 (broad), 1730 (broad), 1230 (broad) cm⁻¹.

Analysis: Calcd. for C₂₄ H₃₄ BrFO₇ (percent) C 54.04; H 6.42; Br 14.98;F 3.56 Found (percent) C 54.23; H 6.46; Br 14.81; F 3.57.

EXAMPLE 45

Using the general procedure of example 44 the16β-methyl-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(IVb) (R₃ =βCH₃) was converted into16β-methyl-2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(Vb) (R₃ =βCH₃)

[α]_(D) ²⁰ +68° (C 1.0 in dioxane)

λmax (methanol) 292 mμ (ε 123)

IR(KBr) 3640, 3460, 3420, 1745, 1735 (broad), 1230 cm⁻¹

Analysis: Calcd. for C₂₄ H₂₄ BrFO₇ (percent) C 54.04; H 6.42; Br 14.98;F 3.56 Found (percent) C 54.25; H 6.43; Br 14.75; F 3.48.

EXAMPLE 46

A solution of 10 g. of 16α-CH₃-2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate(V a) (R₃ =CH₃) in 50 ml. of pyridine was stirred at -5° C. whiledropwise adding 8 g. of methane sulfonyl chloride over a period of about15 min. After addition was completed the mixture was stirred for 1.5 hr.maintaining the temperature at about 0° C., then poured into 400 ml. ofcold water and 200 ml. of dichloroethane. The mixture was acidified atpH 3.5 with 4N sulphuric acid solution and stirred for 1 hr. Thedichloroethane layer was separated, the aqueous portion extracted oncewith 200 ml. of dichloroethane and the combinated organic extractswashed neutral with water, dried and concentrated to dryness undervacuum at 60° C. The yellow oily residue by crystallization frombenzene-hexane gave16α-methyl-2α-bromo-6β-fluoro-5α,11α,17.alpha.,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VIa) (R₃ =αCH₃)

[α]_(D) ²⁰ +30° (C 1.0 in dioxane)

λmax (methanol) 288 mμ (ε 130)

IR(KBr) 3520 (broad), 1730 (broad), 1330, 1230, 1170 cm⁻¹

Analysis: Calcd. for C₂₅ H₃₆ BrFO₉ S (percent) C 49.10; H 5.93; Br13.07; F 3.11 Found (percent) C 48.85; H 5.81; Br 13.23; F 3.20.

EXAMPLE 47

Using the general procedure of example 46 the16β-methyl-2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V b) (R₃ =βCH₃)was converted into16β-methyl-2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate(VI bXR₃ =βCH₃).

M.P. 148°-50° C. (decomposition)

[α]_(D) ²⁰ +60° (C 1.0 in dioxane)

λmax (methanol) 292 mμ (ε 99)

IR(KBr) 3660,3520(broad),3370(broad),1740,1725,1330,1220,1170 cm⁻¹.

Analysis: Calcd. for C₂₅ H₃₆ BrFO₉ S (percent) C 49.10; H 5.93; Br13.07; F 3.11 Found (percent) C 49.23; H 5.89; Br 13.25; F 2.98.

EXAMPLE 48

10 g. of16α-methyl-2α-bromo-6β-fluoro-5α,11α,17.alpha.,21-tetrahydroxy-pregnane-3,20-dione-11-mexylate-21-acetate(VI aXR₃ =αCH₃) were added to a solution of 75 ml. of acetic anhydrideand 0.5 ml. of 70% perchloric acid in 450 ml. of ethyl acetate. Themixture was kept at 30° C. for 0.5 hr. and washed successively with 5%sodium bicarbonate aqueous solution. The ethyl acetate solution afteranhydrification on sodium sulphate was evaporated to dryness undervacuum. Crystallization of the residue from methanol gave about 9 g. of16α-methyl-2α-bromo-6β-fluoro-5α,11α,17.alpha.,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate(VIIaXR₃ =αCH₃) characterized by

M.P. 136°-8° C. (decomposition)

[α]_(D) ²⁰ -3° (C 1.0 in chloroform)

IR(KBr) 1745 (broad), 1365, 1220 (broad), 1170 cm⁻¹.

Analysis: Calcd. for C₂₉ H₄₀ BrFO₁₁ S (percent) C 50.07; H 5.80; Br11.49; F 2.73. Found (percent) C 50.25; H 5.92; Br 11.35; F 2.66.

EXAMPLE 49

Using the general procedure of example 48 the16β-methyl-2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate(VIb) (R₃ =βCH₃) was converted into 16β-methyl-2α-bromo-6β-fluoro-5α,11α,17α,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate(VIIb) (R₃ =βCH₃) characterized by

M.P. 131°-2° C. (decomposition)

[α]_(D) ²⁰ +27° (C 1.0 in chloroform)

IR(KBr) 1750 (broad), 1370, 1220 (broad), 1170 cm⁻¹.

Analysis: Calcd. for C₂₉ H₄₀ BrFo₁₁ S (percent) C 50.07; H 5.80; Br11.49; F 2.73. Found (percent) C 50.15; H 5.72; Br 11.55; F 2.82.

EXAMPLE 50

6.9 g. of16α-methyl-2α-bromo-6β-fluoro-5α,11α,17.alpha.,21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate(VII a) (R₃ =αCH₃) were dissolved in 320 ml. of anhydrous acetic acid at90° C. on the steam bath. A solution of sodium acetate (15 g. dried at100° C.) in acetic acid (60 ml.) at 90° C. was added, followedimmediately by 1.80 g. of bromine in acetic acid (25 ml.), added in onelot. Heating at 90° C. was continued until the bromine colourdisappeared (about 5 min. in all). The solution was then cooled asrapidly as possible to room temperature and poured in cold water. Thesolid was collected by filtration, washed thoroughly with water anddried to a constant weight, giving about 7 g. of16α-methyl-2,2-dibromo-6β-fluoro-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate(VII bis a) (R₃ =αCH₃).

M.P. 135°-7° C. (decomposition)

[α]_(D) ²⁰ -20° (C 1.0 in chloroform)

λmax (methanol) 242-3 mμ (ε 10700)

IR(KBr) 1745, 1730, 1698, 1620, 1330, 1220, 1770 cm⁻¹.

Analysis: Calcd, for C₂₇ H₃₅ Br₂ FO₉ S (percent) C 45.39; H 4.94; Br22.37; F 2.66. Found (percent) C 45.62; H 5.05; Br 22.23; F 2.55.

EXAMPLE 51

Using the general procedure of example 50 the16β-methyl-2α-bromo-6β-fluoro-11α,17α,21-trihydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate(VII bXR₃ =βCH₃) was converted into16β-methyl-2,2-dibromo-6β-fluoro-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate(VII bis b)(R₃ =βCH₃).

M.P. 141°-2° C. (decomposition)

[α]_(D) ²⁰ +12° (C 1.0 in chloroform)

λmax (methanol) 243 mμ (ε10600)

IR(KBr) 1745,1730,1696,1625,1330,1220,1170 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₅ Br₂ FO₉ S (percent) C 45.39; H 4.94; Br22.37; F 2.66. Found (percent) C 45.51; H 4.88; Br 22.48; F 2.52.

EXAMPLE 52

6 g. of16α-methyl-2,2-dibromo-6β-fluoro-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-11mesylate-17,21-diacetate(VII bis aXR₃ =αCH₃) were added in one portion to a mixture of 60 ml. ofdimethylformamide, 12 g. of lithium carbonate and 6 g. of lithiumbromide under stirring at 100° C. The reaction mixture was then refluxedat 130° C. under nitrogen for 0.5 hr., cooled and poured into coldwater. The precipitate was filtered off, washed with water and dried

Crystallization of the residue from acetone-hexane gave 3.5 g. of16α-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(VIII aXR₃ =16αCH₃) characterized by

[α]_(D) ²⁰ -84° (C 1.0 in chloroform)

λmax (methanol) 246-7 mμ (ε 12900)

IR(KBr) 1745,1730,1680,1605,1230 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₀ BrFO₆ (percent) C 58.11; H 5.63; Br 14.87;F 3.53. Found (percent) C58.07; H 5.69; Br 14.79; F 3.47.

EXAMPLE 53

Using the general procedure of example 52 the16β-methyl-2,2-dibromo-6β-fluoro-11α,17α,21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate(VII bis bXR₃ =βCH₃) was converted into16β-methyl-2-bromo-6β-dluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(VIII bXR₃ =βCH₃) characterized by

[α]_(D) ²⁰ -66° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 12430)

IR(KBr) 1760,1740 (broad), 1670,1600,1235 cm⁻¹.

NMR (CDCl₃ -TMS) Hz at 60 mHz 454 (S,1, C-1 H) 376, 372 (d,1,C-4 H)342,288 (doublet of triplets, 1,C-6 H) 340-330 (m,1,C-11 H)298,282,266,250 (doublet or doublets, 2,CH₂ OAc) 130 (S,3,OAc) 126 (S,3,OAc) 96, 94 (d,3,19 CH₃ split by 6βF) 85,78 (d,3,C-16 βCH₃) 46 (S,3,18CH₃)

Analysis: Calcd. for C₂₆ H₃₀ BrFO₆ (percent) C 58.11; H 5.62; Br 14.87;F 3.53. Found (percent) C 58.20; H 5.71; Br 14.92; F 3.47.

EXAMPLE 54

8.5 g. of 1,3-dibromo-5,5-dimethyl-hydantoin were added in the dark at15° C. under stirring over a period of 0.5 hr. to a suspension of 11 g.of16α-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(VIII a) (R₃ =αCH₃) in 250 ml. of tetrahydrofurane and 1.1 g. of 70%perchloric acid in 11 ml. of water. During the addition the suspensionbegan to thin and after a total reaction time of 45 min. all thestarting material was dissolved. After an additional 2 hrs., 10% sodiumsulfite aqueous solution was added under stirring until Kj-starch paperwas no longer blued. The solution was slowly poured into 1000 ml. coldwater, then filtered and utilized moist in the next reaction. The16α-methyl-2,9α-dibromo-6β-fluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(10 a) (R₃ =αCH₃) was filtered and utilized moist in the next reaction.Analytically pure (10 a) was obtained by crystallization fromacetone-hexane.

M.P. 205°-7° C. (decomposition)

IR(KBr) 3470,1760,1730,1670,1640,1610,1230 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₁ Br₂ FO₇ (percent) C 49.23; H 4.93; Br25.19; F 2.99.

Found (percent) C 49.31; H 5.05; Br 25.35; F 3.10.

EXAMPLE 55

Using the general procedure of example XVII the16β-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(VIII b) (R₃ =βCH₃) was converted into16β-methyl-2,9α-dibromo-6β-fluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(10 b) (R₃ =βCH₃) characterized by

M.P. 207°-9° C. (decomposition)

IR(KBr) 3500 (broad), 1740,1725,1675,1645,1600,1235 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₁ Br₂ FO₇ (percent) C 49.23; H 4.93; Br25.19; F 2.99. Found (percent) C 49.37; H 5.10; Br 24.95; F 2.91.

However, the product (10 b) was filtered and utilized moist in the nextreaction.

EXAMPLE 56

50 ml. of a 14% potassium carbonate aqueous solution were added over aperiod of 20 min. at 20° C. under stirring to the solution of the moistproduct (10 a) (R₃ =αCH₃)16α-methyl-2,9α-dibromo-6β-fluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetateobtained in example XVII from 11 g. of the product (9 a) (R₃ =αCH₃) in220 ml. of acetone. The solution was stirred for 3.5 hrs. Ice water wasadded under stirring, upon which crystallization occurs rapidly. Theproduct16α-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11.beta.-oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate(11 a) (R₃ =αCH₃) was filtered, washed with water, dried andcharacterized by

M.P. 232°-4° C. (decomposition)

[α]_(D) ²⁰ -96°, (C 1.0 in chloroform)

IR(KBr) 1755,1735,1675,1645,1610,1235 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₀ BrFO₇ (percent) C 56.43; Br 14.44 F 3.43.Found (percent) C 56.61; H 5.32; Br 14.27; F 3.52.

EXAMPLE 57

Using the general procedure of example 56 the16β-methyl-2,9α-dibromo-6β-fluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(10 b) (R₃ =βCH₃) was converted into16α-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11.beta.-oxido-pregna-1,4,-diene-3,20-dione-17,21-diacetate(11 b) (R₃ =βCH₃) characterized by

M.P. 234°-5° C. (decomposition)

[α]_(D) ²⁰ -53° (C 1.0 in chloroform)

IR(KBr) 1755,1730,1675,1645,1610,1240 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₀ BrFO₇ (percent) C 56.43; H 5.46; Br 14.44;F 3.43. Found (percent) C 56.29; H 5.32; Br 3.37.

EXAMPLE 58

50 ml. of a 70% hydrofluoric acid aqueous solution were cooled to -10°C. in a polyethylene flask equipped with electromagnetic stirrer. 3.7 g.of16α-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11.beta.-oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate(11 a) (R₃ =αCH₃) were added under stirring during 15 min. After 1.5 hr.the reaction mixture was precipitated in water and ammonia. The solidwas collected by filtration, washed with water and dried to a constantweight, giving about 3.5 g. of16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12 a) (X=OH, Y=F, R₁ =R₂ =OCOCH₃, R₃ =αCH₃). Crystallization frombenzene-n-hexane gave 3 g. of pure product characterized by

M.P. 288°-9° C. (decomposition)

[α]_(D) ²⁰ -47° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 12100)

IR(KBr) 3500,1760,1730,1710,1680,1640,1610,1230 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₁ BrF₂ O₇ (percent) C 54.46; H 5.45; Br13.93; F 6.63.

Found (percent) C 54.58; H 5.37; Br 13.80; F 6.75.

EXAMPLE 59

Using the general procedure of example 58 the16β-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11.beta.-pregna-1,4-diene-3,20-dione-17,21-diacetate(11 b) (R₃ =βCH₃) was converted into16β-methyl-2-bromo-6β,α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12 b) (X=OH, Y=F, R₁ =R₂ =OCOCH₃, R₃ =βCH₃), characterized by

[α]_(D) ²⁰ -130° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 12000)

IR(XBr) 3480,1755,1740,1725,1678,1645,1600,1235 cm⁻¹.

Analysis: Calad. for C₂₆ H₃₁ BrF₂ O₇ (percent) C 54.46; H 5.45; Br13.93; F 6.63. Found (percent) C 54.65; H 5.38; Br 14.10; F 6.75.

EXAMPLE 60

50 ml. of hydrochloric acid were added at 0° C. over a period of 40 min.to a solution of 5 g. of16α-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11.beta.-oxido-pregna-1,4-diene-3,20-dione-17,21-diacetate(11 a) (R₃ =αCH₃) in 30 ml. of acetone. The mixture was held at 0° C.with stirring for about 2.5 hrs. and then the precipitate of16α-methyl-2-bromo-6β-fluoro-9α-chloro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12 c) (X=OH, Y=Cl, R₃ =αCH₃, R₁ =R₂ =OCOCH₃) was recovered byfiltration, washed repeatedly with water and dried (4.9 g.). The solidwas crystallized from acetone-hexane and characterized by

M.P. 245°-6° C. (decomposition)

λmax (methanol) 246 mμ (ε 12000)

[α]_(D) ²⁰ -34° (C 1.0 in chloroform)

IR(KBr) 3460,1757,1730,1710,1678,1645,1608,1230 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₁ BrClFO₇ (percent) C 52.94; H 5.30; Br13.54; Cl 6.01; F 3.22. Found (percent) C 53.12; H 5.37; Br 13.71; Cl6.12; F 3.14.

EXAMPLE 61

Using the general procedure of example 60 the16β-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-9β,11.beta.-oxido-1,4-diene-3,20-dione-17,21-diacetate(11 b) (R₃ =βCH₃) was converted into16β-methyl-2-bromo-6β-fluoro-9α-chloro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12 d) (X=OH, Y=Cl, R₁ =R₂ =OCOCH₃, R₃ =βCH₃) characterized by

M.P. 250°-1° C. (decomposition)

λmax (methanol) 246 mμ (ε 12150)

[α]_(D) ²⁰ +2° (C 1.0 chloroform)

IR(KBr) 3480,1740 (broad), 1723,1675,1645,1600,1235 cm⁻¹.

Analysis: Calcd. for C₂₆ H₃₁ BrClFO₇ (percent) C 52.94; H 5.30; Br13.54; Cl 6.01; F 3.22. Found (percent) C 52.73; H 5.32; Br 13.60; cl6.15; F 3.31.

EXAMPLE 62

To a solution of 10 g. of16α-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(9α) (R₃ =αCH₃) and 40 g. lithium chloride in 200 ml. of glacial aceticacid were added at 20° C. under stirring 5 g. of N-chlorosuccinimide.The mixture was kept at 20 C. and stirred while dropwise adding 10 ml.of a 12% hydrochloric acid tetrahydrofurane solution over a period ofabout 10 min. After 3.5 hrs. the reaction mixture was poured into coldwater, the solid was collected by filtration, washed with water anddried, giving 7.5 g. of pure product16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12e) (X=Y=Cl, R₁ =R₂ =OCOCH₃, R₃ =αCH₃) characterized by M.P. 253°-5°C. (decomposition)

[α]_(D) ²⁰ -10° C. (C 1.0 in chloroform) max (methanol) 245 mμ (12350)

IR(KBr) 1745, 1730, 1670, 1645, 1605, 1235 cm⁻¹.

NMR (dimethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 464 (S, 1, C-1 H) 393,398(d, 1, C-4 H) 346,296(doublet of triplets, 1, C-6 H) 318-304 (m, 1, C-11H) 309, 293, 288, 272 (doublet of doublets, 2, CH₂ OAc) 125 (S, 1, OAc)123 (S, 1, OAc) 108,104 (d 3, 19 CH₃ split by 6βF) 65 (S, 3, 18 CH₃)58,51 (d, 3, 16αCH₃).

Analysis: Calcd. for C₂₆ H₃₀ BrCl₂ FO₆ (percent) C 51.33; H 4.97; Br13.14; Cl 11.66; F 3.12. Found (percent) C 51.45; H 5.07; Br 13.04; Cl11.81; F 3.19.

EXAMPLE 63

Using the general procedure of example 62 the16β-methyl-2-bromo-6β-fluoro-17α,21-dihydroxy-pregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate(9 b) (R₃ =βCH₃) was converted into16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 f) (R₁ =R₂=OCOCH₃, R₃ =βCH₃, X=Y=Cl) characterized by M.P. 224°-6° C.(decomposition)

[α]_(D) ²⁰ +21° (C 1.0 in chloroform)

IR(KBr) 1750, 1730, 1675, 1645, 1605, 1230 cm⁻¹.

NMR (diemethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 465 (S, 1, C-1 H) 394,390(d, 1, C-4 H) 348,298 (doublet of triplets 1, C-6 H) 320-305 (m, 1 C-11H) 295,279,270,254 (doublet of doublets, 2, CH₂ OAc) 126 (S, 6, 2xOAc)109, 105 (d, 3, 19CH₃ split by 6βF) 78,72 (d, 3, 16βCH₃) 58 (S, 3, 18CH₃).

Analysis: Calcd. for C₂₆ H₃₀ BrCl₂ FO₆ (percent) C 51.33; H 4.97; Br13.14; Cl 11.66; F 3.12. Found (percent) C 51.55; H 4.82; Br 12.98; Cl11.65; F 3.12.

EXAMPLE 64

A suspension of 5.2 g. of16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12a) (X=CH, Y=F, R₃ =CH₃, R₁ =R₂ =OCOCH₃) in 120 ml. of 1% potassiumhydroxide methanolic solution was stirred under nitrogen at 0° C. for 3hrs. Addition of cold water, elimination of methanol in vacuo,acidification with acetic acid and filtration gave 4 g. of16α-methyl-2-bromo-6β,9α-difluro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (X=OH, Y=F, R₁ =R₂=OH, R₃ =αCH₃)

[α]_(D) ²⁰ -24° (C 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε 12250)

IR(KBr) 3460(broad), 1710, 1665, 1640, 1603 cm⁻¹.

NMR (dimethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 466 (S, 1, C-1 H) 388,384(d, 1, C-4 H) 345,295 (doublet of triplets, 1, C-6 H) 318-314 (d, 1,C-11 OH) 296 (S,,1C-17 OH) 280-225 (multiplet which becomes a quartet bydeuterium exchange, 2, COCH₂ OH) 96,94 (d,3,19 CH₃ split by 6βF) 54(S,3,18, CH₃) 54,44 (d,3,C-16αCH₃)

Analysis: Calcd. for C₂₂ H₂₇ BrF₂ O₅ (percent) C 53.99; H 5.56; Br16.33; F 7.76. Found (percent) C 54.10; H 5.70; Br 16.41; F 7.85.

EXAMPLE 65

Using the general procedure of example 64 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12 b) (X=OH, Y=F, R₁ =R₂ =OCOCH₃, R₃ =βCH₃) was converted into16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pergna-1,4-diene-3,20-dione(12 h) (X=OH, Y=F, R₁ =R₂ =OH, R₃ =βCH₃).

M.P. 216°-7° C. (decomposition)

[α]_(D) ²⁰ +11° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 10900)

IR(KBr) 3440 (broad), 1715, 1665, 1640, 1600 cm⁻¹.

NMR (dimethyl-d₆ sulfoxide-TMS) Hz at 60 mHz 472 (S, 1, C-1 H) 388,384(d, 1, C-4 H) 346,296 (doublet of triplets, 1, C-6 H) 339-334 (m, 1,C-11 OH) 315 (S, 1, C-17 OH) 280-240 (multiplet which becomes a quartetby deuterium exchange, 2, COCH₂ OH) 96,94 (d, 3, 19 CH₃ split by 6βF)65,58 (d, 3, C-16βCH₃) 58 (S, 3, 18 CH₃).

Analysis: Calcd. for C₂₂ H₂₇ BrF₂ O₅ (percent) C 53.99; H 5.56; Br16.33; F 7.76. Found (percent) C 53.75; H 5.45; Br 16.41; F 7.87.

EXAMPLE 66

Using the general procedure of example 64 the16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12 e) (R₁ =R₂ =OCOCH₃, R₃ =αCH₃, X=Y=Cl) was converted into16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17α,21-dihydroxy-pregna-1,4-diene-3,20-dione(12 i) (R₁ =R₂ =OH, R₃ =CH₃, X=Y=Cl).The product was crystallized fromacetone-hexane.

M.P. 216°-8° C.

[α]_(D) ²⁰ +21° (C 1.0 in chloroform)

IR(KBr) 3640, 3500, 3400, 1705, 1665, 1642, 1605 cm⁻¹.

Analysis: Calcd. for C₂₂ H₂₆ BrCl₂ FO₄ (percent) C 50.40; H 4.99; Br15.24; Cl 13.52; F 3.62. Found (percent) C 50.63; H 5.12; Br 15.34; Cl13.68; F 3.61.

EXAMPLE 67

Using the general procedure of example 66 the16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(12 d) (R₁ =R₂ =OCOCH₃, R₃ =βCH₃, X=Y=Cl) was converted into16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione(12 j) (R₁ =R₂ =OH, R₃ =βCH₃, X=Y=Cl)

[α]_(D) ²⁰ +51° (C 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε 11500)

IR(KBr) 3600, 3480, 3360, 1710, 1665, 1645, 1610 cm⁻¹.

Analysis: Calcd. for C₂₂ H₂₆ BrCl₂ FO₄ (percent) C 50.40; H 4.99; Br15.24; Cl 13.52; F 3.62. Found (percent) C 50.35; H 4.81; Br 15.20; Cl13.31; F 3.68.

EXAMPLE 68

7 g. of16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) were dissolved in 70 ml. ofpyridine containing 35 ml. of acetic anhydride and kept at roomtemperature for 12 hrs. Addition of ice water afforded a product whichwas extracted with chloroform. The chloroform solution was washed withwater, 2NHCl, 5% sodium bicarbonate solution and water.

After drying (Na₂ SO₄) and removal of the solvent in vacuo the residuewas crystallized from acetone-hexane to give 6.7 g. of16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-21-acetate(12 k) (R₁ =OCOCH₃, R₂ =OH, X=OH, Y=F, R₃ =αCH₃)

M.P. 229°-31° C.

[α]_(D) ²⁰ -6.3° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11300)

IR(KBr) 3520 (broad), 1740, 1720, 1665, 1640, 1605, 1230 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₆ (percent) C 54.25; H 5.50; Br15.04; F 7.15. Found (percent) C 54.41; H 5.60; Br 14.95; F 7.12.

EXAMPLE 69

Using the general procedure of example 68 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 h) (R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(12 l) (R₁ =OCOCH₃, R₃ =OH, X=OH, Y=F, R₃ =βCH₃).

M.P. 216°-8° C.

[α]_(D) ²⁰ +25° (C. 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε 11500)

IR(KBr) 3500 (broad), 1745, 1720, 1675, 1645, 1610, 1230 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₆ (percent) C 54.25; H 5.50; Br15.04; F 7.15. Found (percent) C 54.45; H 5.38; Br 15.11; F 7.08.

EXAMPLE 70

Using the general procedure of example 68 the16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate(12 m) (R₁ =OCOCH₂ CH₃, R₂ =OH, R₃ =αCH₃, X=OH, Y=F) by reaction withpropionic anhydride.

[α]_(D) ²⁰ +4° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 10800)

IR(KBr) 3520 (broad), 1740, 1728, 1672, 1645, 1605, 1225 cm⁻¹.

Analysis: Calcd. for C₂₅ H₃₁ BrF₂ O₆ (percent) C 55.05; H 5.73; Br14.65; F 6.97. Found (percent) C 55.25; H 5.62; Br 14.55; F 7.07.

EXAMPLE 71

Using the general procedure of example 68 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 h) (R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate(12 n) (R₁ =OCOCH₂ CH₃, R₂ =OH, R₃ =βCH₃, X=OH, Y=F) by reaction withpropionic anhydride.

[α]_(D) ²⁰ +27° (C 1.0 in chloroform)

λmax (methanol 246 mμ (ε 11000)

IR(KBr) 3500 (broad), 1745, 1730, 1670, 1645, 1605, 1220 cm⁻¹.

Analysis: Calcd. for C₂₅ H₃₁ BrF₂ O₆ (percent) C 55.05; H 5.73; Br14.65; F 6.97. Found (percent) C 55.10; H 5.72; Br 14.85; F 7.08.

EXAMPLE 72

Using the general procedure of example 68 the16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione(12 i) (R₁ =R₂ =OH, R₃ =αCH₃, X=Y=Cl) was converted into16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(12 o) (R₁ =OCOCH₃, R₂ =OH, R₃ =αCH₃, X=Y=Cl). The product wascrystallized from methanol. The crystals showed at 158° C. a transactionfrom the low melting form II to the form I melting 237°-8° C. (decomp.)

[α]_(D) ²⁰ +32° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε 11550)

IR(KBr) 3550, 3460, 3340, 1755, 1730, 1673, 1635, 1605, 1230 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₈ BrCl₂ FO₅ (percent) C 50.90; H 4.98; Br14.11; Cl 12.52; F 3.35. Found (percent) C 51.12; H 5.05; Br 13.98; Cl12.40; F 3.28.

EXAMPLE 73

Using the general procedure of example 68 the16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione(12 j) (R₁ =R₂ =OH, R₃ =βCH₃, X=Y=Cl) was converted into16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(12 p) (R₁ =OCOCH₃, R₂ =OH, R₃ =βCH₃, X=Y=Cl).

[α]_(D) ²⁰ +61° (C 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε 11000)

IR(KBr) 3500 (broad), 1750, 1730, 1675, 1645, 1605, 1230 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₈ BrCl₂ FO₅ (percent) C 50.90; H 4.98; Br14.11; Cl 12.52; F 3.35. Found (percent) C 51.12; H 4.88; Br 13.95; Cl12.41; F 3.28.

EXAMPLE 74

A mixture of 5 g. of16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F), 5 ml. of dimethylformamide wasmaintained for 4 hrs. under nitrogen at 115° C. Then the mixture wasneutralized by pyridine and concentrated under vacuum to dryness.Purification by column chromatography on FLORISIL (Registered TradeMark) (ratio 1:150) with benzene-chloroform (1:1) as eluant, gave 4 g.of16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-(1'-methoxy)-n-pentylidenodioxywhich, without further purification, was suspended in 25 ml. of methanoland 3 ml. 1 N hydrochloric acid aqueous solution, heated on water bathat 40°-50° C.

After complete solubilization of the product, the mixture wasconcentrated under vacuum. The insoluble product was filtered off,washed with water and then dried.

The16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate(12 q) (Z=H, R₁ =OH, R₂ =OCOCH₂)₃ CH₃. R₃ =H, X=OH, Y=F) thus obtainedwas characterized by

[α]_(D) ²⁰ -92° (C 1.0 in chloroform)

λmax (mehtanol) 246 mμ (ε 12300)

IR(KBr) 3500 (broad), 1730, 1715, 1672, 1640, 1605 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₆ BrF₂ O₆ (percent) C 56.55; H 6.15; Br13.93; F 6.63. Found (percent) C 56.67; H 6.05; Br 14.12; F 6.75.

EXAMPLE 75

Using the general procedure of example 74 the16α-methyl-2-bromo-6β,9α-difluoro-11β,17α21-trihydroxy-pregna-1,4-diene-3,20-dione(12g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 r) (R₁ =OH, R₂ =OCOCH₃, R₃ =αCH₃, X=OH, Y=Z)

M.P. 212°-4° C. (decomposition)

[α]_(D) ²⁰ -91° (C 1.0 in chloroform)

λmax (methanol 245-6 mμ (ε12100)

IR(KBr) 3450 (broad), 1725, 1710, 1680, 1640, 1610, 1250 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₆ (percent) C 54.29; H 5.50; Br15.04; F 7.15. Found (percent) C 54.48; H 5.57; Br 15.18; F 7.20.

EXAMPLE 76

Using the general procedure of example 74 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 h)(R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate(12 s) (R₁ =OH, R₂ =OCO(CH₂)₃ CH₃, R₃ =βCH₃,X=OH, Y=Z).

[α]_(D) ²⁰ -60° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε12000)

IR(KBr) 3480 (broad), 1730, 1710, 1675, 1640, 1610 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₅ BrF₂ O₆ (percent) C 56.55; H 6.15; Br13.93; F 6.63. Found (percent) C 56.80; H 6.08; Br 13.83; F 6.75.

EXAMPLE 77

Using the general procedure of example 74 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-(12h) (R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 t) (R₁ =OH, R₂ =OCOCH₃, R₃ =βCH₃, X=OH, Y=Z).

M.P. 227°-8° C. (decomposition)

λmax (methanol) 246 mμ (ε11100)

IR(KBr) 3500 (broad), 1670, 1642, 1605, 1230 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₉ BrF₂ O₆ (percent) C 54.25; H 5.50; Br15.04; F 7.15. Found (percent) C 53.97; H 5.61; Br 15.24; F 7.27.

EXAMPLE 78

Using the general procedure of example 74 the16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione(12 i) (R₁ =R₂ =OH, R₃ =αCH₃, X=Y=Cl) was converted into16α-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate(12 u) (R₁ =OH, R₂ =OCOCH₃, R₃ =αCH₃, X=Y=Cl).

M.P. 245°-7° C. (decomposition)

[α]_(D) ²⁰ -43° (C 1.0 in chloroform)

λmax (methanol) 245 mμ (ε11750)

IR(KBr) 3500, 1720, 1710, 1675, 1640, 1607 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₈ BrCl₂ PO₅ (percent) C 50.90; H 4.98; Br14.11; Cl 12.52; F 3.35. Found (percent) C 51.12; H5.07; Br 13.97; Cl12.30; F. 3.27.

EXAMPLE 79

Using the general procedure of example 74 the16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione(12 h) (R₁ =OH, R₂ =OCOCH₃, R₃ =βCH₃, X=Y=Cl) was converted into16β-methyl-2-bromo-6β-fluoro-9α,11β-dichloro-17.alpha.,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12 v) (R₁ =OH, R₂ =OCOCH₃, R₃ =βCH₃, X=Y=Cl).

[α]_(D) ²⁰ -12° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε11600)

IR(KBr) 3500 (broad), 1720, 1710, 1670, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₄ H₂₈ BrCl₂ FO₅ (percent) C 50.90; H 4.98; Br14.11; Cl 12.52; F 3.35. Found (percent) C 51.15; H 5.19; Br 14.05; Cl12.47; F 3.28.

EXAMPLE 80

A solution of 6 g. of 16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (R₁ =R₂ =OH, R₃ =αCH₃) in12 ml. of dimethylformamide and 40 ml. of 2,2-dimethoxypropane with0.030 g. of p-toluenesulfonic acid was heated for 5 hrs. at 115° C. Thereaction mixture was cooled, poured in 10% sodium bicarbonate aqueoussolution and chloroform. The chloroform solution was then washed withwater, dried and evaporated to a residue which by crystallization fromacetone-hexane gave 5 g. of16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-diene-17,21-acetonide(12 w) characterized by

[α]_(D).sup.° -18° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε11950)

IR(KBr) 3480 (broad), 1725, 1678, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₅ H₃₁ BrF₂ O₅ (percent) C 56.72; H 5.90; Br15.09; F 7.18. Found (percent) C 56.90; H 6.08; Br 15.25; F 7.27.

EXAMPLE 81

Using the general procedure of example 80 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 h) (R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide(12z) characterized by

[α]_(D) ²⁰ +14° (C 1.0 in chloroform) λmax (methanol) 246 mμ (ε12000)

IR(KBr) 3475 (broad), 1720, 1675, 1640, 1605 cm⁻¹.

Analysis: Calcd. for C₂₅ H₃₁ BrF₂ O₅ (percent) C 56.72; H 5.90; Br15.09; F 7.18. Found (percent) C 56.91; H 5.73; Br 14.89; F 7.12.

EXAMPLE 82

Using the general procedure of Example 68 the16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate(12 aa) (R₁ =OCO(CH₂)₃ CH₃, R₂ =OH, R₃ =αCH₃, X=OH, Y=F) by reactionwith valeric anhydride.

[α]_(D) ²⁰ +10° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε11700)

IR(KBr) 3500 (broad), 1740, 1725, 1670, 1640, 1605, 1230 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₅ BrF₂ O₆ (percent) C 56.55; H 6.15; Br13.93; F 6.62. Found (percent) C 56.48; H 6.21; Br 14.05; F 6.55.

EXAMPLE 83

Using the general procedure of Example 68 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 h)(R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,9α-difluror-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate(12 ab) (R₁ =OCO(CH₂)₃ CH₃, R₂ =OH, R₃ =βCH₃, X=OH, Y=F) by reactionwith valeric anhydride.

[α]_(D).sup.° +39° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε11800)

IR(KBr) 3520 (broad), 1745, 1730, 1670, 1645, 1605, 1230 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₅ BrF₂ O₆ (percent) C 56.55; H 6.15; Br13.93; F 6.62. Found (percent) C 56.61; H 6.05; Br 13.89; F 6.70.

EXAMPLE 84

Using the general procedure of Example 68 the16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydoxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12 ac) (R₁ =OCOC(CH₃)₃, R₂ =OH, R₃ =αCH₃, X=OH, Y=F)by reaction with pivalic anhydride.

[α]_(D) ²⁰ +5° (C 1.0 in chloroform)

λmax (methanol) 245-6 mμ (ε10850)

IR(KBr) 3480 (broad), 1740, 1730, 1670, 1645, 1605, 1225 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₅ BrF₂ O₆ (percent) C 56.55; H 6.15; Br13.93; F 6.62. Found (percent) C 56.60; H 6.12; Br 13.95; F 6.55.

EXAMPLE 85

Using the general procedure of Example 68 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 h) (R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,6α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate(12 ad) (R₁ =OCOC(CH₃)₃, R₂ =OH, R₃ βCH₃, X=OH, Y=F) by reaction withpivalic anhydride.

[α]_(D).sup.° +36° (C 1.0 in chloroform)

λmax (methanol) 246≧6 mμ (ε11000)

IR(KBr) 3490 (broad), 1740, 1730, 1670, 1640, 1600, 1230 cm⁻¹.

Analysis: Calcd. for C₂₇ H₃₅ BrF₂ O₆ (percent) C 56.55, H 6.15; Br13.93; F 6.62. Found (percent) C 56.70; H 6.23; Br 14.08; F 6.75.

EXAMPLE 86

Using the general procedure of Example 68 the16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(12 ae) (R₁ =OCOC₆ H₅, R₂ =OH, R₃ =αCH₃, X=OH, Y=F) by reaction withbenzoic anhydride

[α]_(D) ²⁰ ÷75° (C 1.0 in chloroform)

λmax (methanol) 234 mμ (ε22500)

IR(KBr) 3600, 3430 (broad), 1730, 1710, 1670, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₉ H-hd 31BrF₂ O₆ (percent) C 58,69; H 5.26; Br13.46; F 6.40. Found (percent) C 58.85; H 5.35; Br 13.37; F 6.30.

EXAMPLE 87

Using the general procedure of Example 68 the16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 β) (R₁ =R₂ =OH, R₃ =βCH₃, X=OH, Y=F) was converted into16β-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate(12 af) (R₁ =OCOC₆ H₅, R₂ =OH, R₃ =βCH₃, X=OH, Y=F) by reaction withbenzoic anhydride.

[α]_(D) ²⁰ ÷106° (C 1.0 in chloroform)

λmax (methanol) 234 mμ (ε22700)

IR(KBr) 3580, 3420 (broad), 1725, 1710, 1670, 1640, 1600 cm⁻¹.

Analysis: Calcd. for C₂₉ H₃₁ BrF₂ O₆ (percent) C 58.69; H 5.26; Br13.46; F 6.40. Found (percent) C 58.78; H 5.15; Br 13.27; F 6.25.

EXAMPLE 88

Using the general procedure of Example 74 the16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₂ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate(12 ag) (R₁ =OH, R₂ =OCOCH₂ CH₃, R₃ =αCH₃, X=OH, . Y=F)

[α]_(D) ²⁰ -92° (C 1.0 in chloroform)

λmax (methanol) 246 mμ (ε12100)

IR(KBr) 3500, 3430, 1730, 1710, 1675, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₅ H₃₁ BrF₂ O₆ (percent) C 55.05; H 5.73; Br14.65; F 6.97. Found (percent) C 55.15; H 5.68; Br 14.47; F 7.02.

EXAMPLE 89

Using the general procedure of Example 74 the16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(12 g) (R₁ =R₂ =OH, R₃ =αCH₃, X=OH, Y=F) was converted into16α-methyl-2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate(12 ah) (R₁ =OH, R₂ =OCOC₆ H₅, R₃ =αCH₃, X=OH, X=F)

[α]_(D) ²⁰ -120° (C 1.0 in chloroform)

λmax (methanol) 234 mμ (ε23000)

IR(KBr) 3490, 3420, 1730, 1710, 1678, 1645, 1605 cm⁻¹.

Analysis: Calcd. for C₂₉ H₃₁ BrF₂ O₆ (percent) C 58,69; H 5.26; Br13.46; F 6.40. Found (percent) C 58.75; H 5.18; Br 13.35; F 6.30.

EXAMPLE 90

Topical cream formulations containing variable percentages of2-bromo-6β,9α-difluoro-11β,17α21-trihydroxy-1,4-diene-3,20-dione17,21-diacetate (XI).

    ______________________________________                                        Ingredients           Percent range(w/w)                                      ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-                                             dione 17,21-diacetate 0.005-0.5                                               Cetostearyl alcool     5-20                                                   Polysorbate 60        1-5                                                     Polysorbate 80        1-5                                                     Isopropyl miristate    5-15                                                   Gliceryl monostearate 1-5                                                     Sorbitol solution      1-10                                                   Preservatives         0,2-0,5                                                 Distilled water       q.s.ad 100                                              ______________________________________                                    

The ingredients are mixed in a conventional manner for preparing apharmaceutical topical cream.

If desired, an antibacterial component such as neomycin may be added tothe formulation in amount ranging from 0.1% to 3%.

EXAMPLE 91

Topical ointment formulations containing variable percentages of2-bromo-6β,9α-difluoro-11β,17α21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI).

    ______________________________________                                        Ingredients           Percent range (w/w)                                     ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-                                             dione-17,21-diacetate 0.005-0.5                                               white petrolatum      q.s. ad. 100                                            ______________________________________                                    

The ingredients are blended in a conventional manner providing acolorless topical ointment.

If desired, an antibacterial component such as neomycin may be added tothe formulation in amount ranging from 0.1% to 3%.

EXAMPLE 92

Topical gel formulations containing variable percentages of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI).

    ______________________________________                                        Ingredients           Precent range (w/w)                                     ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-                                             dione-17,21-diacetate 0.005-05                                                Corbopol 934          0.5-2.5                                                 Di-isopropanolamine   0.2-1                                                   Propylene glycol       5-50                                                   Polysorbate 80        0.5-5                                                   Potassium sorbate     0.05-0.25                                               Distilled water       q.s. ad 100                                             ______________________________________                                    

The ingredients are mixed in a conventional manner for preparing apharmaceutical topical gel.

EXAMPLE 93

Topical lotion formulations containing variable percentages of2-bromo6β,9α-difluoro-11β,17α,21-trihydroxy-pregne-1,4-diene-3,20-dione-17,21-diacetate(XI).

    ______________________________________                                        Ingredients            Percent range (w/w)                                    ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-dione-                                       17,21-diacetate        0.005-0.5                                              Propylene glycol        5-35                                                  Cetostearyl alcool     0.5-2                                                  Isopropyl miristate    0.5-2                                                  Eumulgin C-700         0.25-1                                                 Potassium sorbate      0.05-0.25                                              Distilled water        q.s. ad 100                                            ______________________________________                                    

The ingredients are mixed in a conventional manner providing a topicallotion.

If desired, an antibacterial component such as neomycin may be added tothe formulation in amount ranging from 0.1% to 3%.

EXAMPLE 94

Ophthalmic (otic) ointment containing variable percentages of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate(XI).

    ______________________________________                                        Ingredients            Percent range (w/w)                                    ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-dio-                                         ne-17,21-diacetate     0.005-0.5                                              Mineral oil             1-10                                                  White petrolatum       q.s. ad 100                                            ______________________________________                                    

Ingredients are blended in a conventional manner providing an ophthalmicor otic preparation.

If an antibacterial ingredient is desired, neomycin may be added as themicronized sulfate salt.

EXAMPLE 95

Tablets containing variable amount of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxy-pregna-1,4-diene-3,20-dione(XIa).

    ______________________________________                                                               Amount in mg                                           Ingredients            per 200 mg tablet                                      ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-dione                                                                1-50                                                  Starch                 99-75                                                  Lactose                90-65                                                  Talc                   8                                                      Magnesium stearate     2                                                      ______________________________________                                    

The active compound, starch and lactose are blended and compressed intoslugs which are then granulated.

Talc and magnesium stearate are added to the granulated mixture which iscompressed into tablets weighing 0.200 g. Each tablet contains 1-50 mgof active compound.

EXAMPLE 96

Oral suspension containing variable amount of2-bromo-6β,9α-difluoro-11β,17α21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate(XIc).

    ______________________________________                                                                100 ml of                                             Ingredients             suspension (w/v)                                      ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-dione-                                       21-acetate              0.010-0.5                                             Tragacanth gum          0-3                                                   Glycerol                3                                                     Tween 80                0.1                                                   Sucrose                 50                                                    Methylparaben            0.15                                                 Propylparaben            0.05                                                 Flavours and colours    9.5                                                   Distilled water         q.s. ad 100                                           ______________________________________                                    

The ingredients are mixed in a conventional manner to provide aflavoured suspension.

EXAMPLE 97

Suspension for injections containing variable amount of2-bromo-6β,9α-difluoro-11β,17α,21-trihydroxypregna-1,4-diene-3,20-dione-21-acetate(XIc).

    ______________________________________                                                                100 ml of                                             Ingredients             suspension (w/v)                                      ______________________________________                                        2-bromo-6β,9α-difluoro-11β,17α,21-                      trihydroxy-pregna-1,4-diene-3,20-dione-                                       21-acetate              0.5-10                                                Sodium CMC              0.75                                                  Sodium chloride         0.65                                                  Polysorbate 80          0.04                                                  Benzyl alcohol           0.9                                                  Distilled water         q.s. ad 100                                           ______________________________________                                    

The ingredients are mixed in a conventional manner to provide a sterilesuspension of the active compound in very fine particles.

Compositions of all the other compounds of the invention, and inparticular those named specifically above, may be made by replacing theactive ingredients in each of Examples 91 to 97 with any one of theother named compounds.

We claim:
 1. In a process for preparing 2-bromo-6β-fluoropregna-1,4-dien-3,20-dione compounds having the formula A ##STR4##wherein X represents Br, Cl, or OQ; Y represents Br, Cl, F or H; R₁represents OQ; R₂ represents OQ; R₃ represents H, CH₃ or α-OQ; and thegroups Q, which may be the same or different from each other, representH or acyl or the two OQ groups in 16- and 17-position or the two OQgroups in 17- and 21-position together form a cyclic ketal, cyclicacetal or cyclic alkyl orthorester, wherein at least one group OQ is acarboxylic or inorganic acid radical, by ketalizing a compound offormula I ##STR5## wherein R₃ ' is hydrogen or methyl and Ac is CH₃ COunder migration of the double bond into 5,6-position, epoxidizing thedouble bond and reacting the resulting 5α6β-epoxide with hydro-fluoricacid to form a fluoro hydrin compound of formula IV ##STR6## wherein R₃' and Ac are as defined above converting the compound of (IV) into acompound of formula VIII ##STR7## wherein R₃ ' and Ac are as definedabove introducing the substituents X and Y in 9- and 11-position of thecompound of formula VIII and converting the OAc groups in 17- and21-position into a group OQ to form a compound of formula A' ##STR8##wherein X, Y, R₁, R₂ and R₃ ' are as defined above, and dehydrating acompound of formula A' wherein R₃ ' is hydrogen and X, R₁ and R₂ eachare hydroxy to form a compound of formula ##STR9## oxidizing thecompound of formula XIc into the corresponding 16, 17 dihydroxy compoundand converting the 16, 17 and 21 hydroxy groups therein into a group OQto obtain a compound of formula A" ##STR10## wherein X, Y, R₁ and R₂ areas defined above and R₃ " is OQ, wherein the improvement comprises theconversion of a compound of formula IV into a compound of formula VIIIcomprising the steps of(a) monobrominating the compound of formula IVinto a corresponding 2α-bromo compound of the formula V ##STR11##wherein R₃ ' and Ac are as defined above, (b) mesylating the 11-hydroxygroup of the compound of formula V and acetylating the resulting11-mesylate into a compound of formula VII ##STR12## wherein R₃ ' and Acare as defined above and MS represents CH₃ SO₂ --, (c) brominating thecompound of formula VII under dehydroacetylation into a compound offormula VII bis ##STR13## wherein R₃ ' Ac and MS are as defined above,and (d) dehydrobrominating the compound (VIII bis) underdehydromesylation into the compound of formula VIII.
 2. The process asdefined in claim 1 wherein in step (a) the monobromination is carriedout with bromine in a buffered reaction medium.
 3. The process asdefined in claim 2 wherein the monobromination is carried out withbromine in sodium-acetate buffered dioxane.
 4. The process as defined inclaim 1 wherein in step (c) the bromination is carried out with brominein acetic acid containing sodium or potassium acetate.
 5. The process asdefined in claim 1 wherein in step (d) the compound of formula VII bisis treated with a combination comprising a metal halide and an amidesolvent.
 6. The process as defined in claim 1 wherein the metal halideis lithium chloride, lithium bromide or mixtures thereof.
 7. The processas defined in claim 6 wherein the combination further comprises lithiumcarbonate.
 8. The process as defined in claim 6 wherein the amidesolvent is selected from the group consisting of dimethylformamide,dimethylacetamide, N-formylpiperidine, and mixtures thereof.
 9. Theprocess as defined in claim 8 wherein the compound of formula VII bis istreated with a combination of lithium bromide and lithium carbonate indimethylformamide.